Examples of previous research projects

  1. Characterisation of mutant Neuropilin – Endothelial Cells
  2. Role of Novel Neuropilin-associated Proteins (NAPs) in Endothelial Cells
  3. Regulation and Functional Role of Neuropilin-1 Processing in Endothelial Cells
  4. Cardioprotection by autophagy in ischaemia-reperfusion injury
  5. Multiphoton imaging of cardiac responses to ischaemia and reperfusion
  6. Small animal cardiac MRI to investigate
  7. Keeping your mitochondria in shape to protect your heart
  8. Cardioprotection: Bench to Bedside
  9. Voltage Gated Sodium Channels – Structure and Function
  10. Fine scale Genotype mapping of the SH3B3 gene SNPs in relationship to LDL-C levels and CHD risk
  11. The role of adipose tissue cytokines (adipokines) in the link between obesity, depression and cardiovascular disease
  12. Role of nutrition in explaining socioeconomic inequalities in CHD risk factors
  13. Do salivary cotinine levels distinguish smokers who also report exposure to other people’s smoke, and does this increase their cardiovascular risk?
  14. Disability and on going risk factor levels in people with a previous stroke
  15. Changes in social inequalities in obesity and other cardiovascular risk factors over time
  16. Do time trends in cholesterol levels vary by age or by BMI (body mass index) category?
  17. Do overweight and obese children have high blood pressure?
  18. Gender and socioeconomic differences in the onset and diagnosis of  cardiovascular disease at old age
  19. Associations between objectively measured sitting and cardiovascular risk factors
  20. C-reactive protein and physical activity
  21. Risk of specific coronary phenotypes in large populations
  22. Using genetic studies in populations as naturally randomised trials for drug development
  23. RNA Interference of E2F Transcription Factors as a Potential Therapeutic Modality for Neointimal Hyperplasia
  24. Analysing the role of transcriptional regulator, Brn-3b/POU4F2, in developmental and pathological hypertrophy
  25. The regulation of cardiac and vascular smooth muscle cell excitability by ion channels and G-proteins
  26. PPAR as a therapeutic target for prostacyclin analogues in proliferative lung disease
  27. Phosphorylation of the nuclear receptor LXRα induced by agonists with different metabolic actions
  28. Identifying the functional SNPs in the CELSR2/SORT1 locus, associated with differences in LDL cholesterol levels
  29. Regulation of HIF-mediated angiogenesis by HDM2
  30. Validating embryonic/cardiac downstream targets of Thymosin β4
  31. Optimising microsphere uptake RNAi knockdown in embryonic and adult epicardium-derived progenitor cells
  32. Investigating the role of Prox1 in the cardiac lymphatic vasculature
  33. Tissue specific requirements for he chromatin remodeler Chd7 during heart development
  34. Developing novel models to study embryonic pharyngeal surface ectoderm as a signalling centre
  35. Protein interactions of Hic2
  36. Investigation of a novel protein that modifies TGF - β signalling and promotes retinal angiogenesis
  37. Novel roles for VEGF and neuropilin signalling in physiological angiogenesis and the control of cardiovascular tone
  38. Vascular endothelial growth factor (VEGF) signalling in microvascular endothelial cells
  39. Making new blood vessels from embryonic stem cells
  40. Control of brain blood flow by neurotransmitters
  41. Harnessing synergy between natriuretic peptides and phosphodiesterase 5 inhibitors for the treatment of heart failure
  42. The effect of acute exercise on psychobiological responses in participants with depressive symptoms
  43. Development of percultaneous heart valve with nanocomposite polymer peptides and stem cells

1. Characterisation of mutant Neuropilin-1 Endothelial Cells

Supervisor(s):
Professor Ian Zachary
Dr Birger Herzog

Department:
Centre for Cardiovascular Biology and Medicine
Research Department of Cardiovascular Medicine

Project outline (5-10 lines):
The VEGF receptor, Neuropilin-1 (NRP1), plays a key role in VEGF signalling and in angiogenesis, but precisely NRP1 functions as a VEGF co-receptor is poorly understood. We have generated knock-in mice expressing a NRP1 mutant which is unable to bind VEGF. The aim of this project will be to culture endothelial cell from these mutant mice, and compare their biological responses to VEGF with those of endothelial cells cultured from wild-type littermates.

Key reference(s) (max. of 5):

  1. Cheng L Jia H, Löhr M,  Bagherzadeh A, Holmes DIR, Selwood D and Zachary I (2004) Anti-chemorepulsive effects of vascular endothelial growth factor and placental growth factor-2 in dorsal root ganglion neurons are mediated via neuropilin-1 and cyclooxygenase-derived prostanoid production. J Biol Chem. 279:30654-30661.
  2. Holmes DIR and Zachary IC (2008) Vascular Endothelial Growth Factor Regulates Stanniocalcin-1 Expression via Neuropilin-1-dependent Regulaton of KDR and synergism with Fibroblast Growth factor-2. Cell Signal. 20:569-79.
  3. Jia H, Bagherzadeh A, Hartzoulakis B, Jarvis A, Löhr M, Shaikh S, Aqil R, Cheng L, Tickner M, Esposito D, Harris R, Driscoll PC,  Selwood D and Zachary I (2006) Characterisation Of A Bicyclic Peptide Neuropilin-1 (NP-1) Antagonist (EG3287) Reveals Importance Of Vascular Endothelial Growth Factor Exon 8 For NP-1 Binding And Role Of NP-1 In KDR Signalling. J Biol Chem 281:13493-13502.
  4. Pellet-Many C, Paul Frankel P, Jia H, and Zachary IC (2008) Neuropilins: Structure, Function and Role in Disease. Biochem J. 411: 211-226
  5. Frankel P, Pellet-Many C, Lehtolainen P, D'Abaco GM, Tickner M, Cheng L, and Zachary IC (2008) Chondroitin sulphate modified Neuropilin-1 is expressed in human tumour cells and modulates 3D invasion in the U87MG human glioblastoma cell line via a p130Cas mediated pathway. EMBO Rep. 9:983-989.

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2. Role of Novel Neuropilin-associated Proteins (NAPs) in Endothelial Cells

Supervisor(s):

Professor Ian Zachary
Dr Paul Frankel

Department:
Centre for Cardiovascular Biology and Medicine
Research Department of Cardiovascular Medicine

Project outline (5-10 lines):
The VEGF receptor, Neuropilin-1 (NRP1), plays a key role in VEGF signalling and in angiogenesis, but the mechanism(s) mediating NRP1 functions in endothelial cells remain poorly understood. Using a yeast two-hybrid screen with the NRP1 cytosolic domain as the bait protein, we have identified several novel Neuropilin-associated Proteins (NAPs). This project aims to examine the interaction between selected NAPs and NRP1 in human endothelial cells using co-immunoprecipitation, and confocal imaging of immunofluorescent staining. Further work will examine the functional relevance of NAPs for VEGF and NRP1 function by expression of NAP-targeted siRNAs and by over-expression of NAPs in endothelial cells.

Key reference(s) (max. of 5):

  1. Cheng L Jia H, Löhr M,  Bagherzadeh A, Holmes DIR, Selwood D and Zachary I (2004) Anti-chemorepulsive effects of vascular endothelial growth factor and placental growth factor-2 in dorsal root ganglion neurons are mediated via neuropilin-1 and cyclooxygenase-derived prostanoid production. J Biol Chem. 279:30654-30661.
  2. Holmes DIR and Zachary IC (2008) Vascular Endothelial Growth Factor Regulates Stanniocalcin-1 Expression via Neuropilin-1-dependent Regulaton of KDR and synergism with Fibroblast Growth factor-2. Cell Signal. 20:569-79.
  3. Jia H, Bagherzadeh A, Hartzoulakis B, Jarvis A, Löhr M, Shaikh S, Aqil R, Cheng L, Tickner M, Esposito D, Harris R, Driscoll PC,  Selwood D and Zachary I (2006) Characterisation Of A Bicyclic Peptide Neuropilin-1 (NP-1) Antagonist (EG3287) Reveals Importance Of Vascular Endothelial Growth Factor Exon 8 For NP-1 Binding And Role Of NP-1 In KDR Signalling. J Biol Chem 281:13493-13502.
  4. Pellet-Many C, Paul Frankel P, Jia H, and Zachary IC (2008) Neuropilins: Structure, Function and Role in Disease. Biochem J. 411: 211-226
  5. Frankel P, Pellet-Many C, Lehtolainen P, D'Abaco GM, Tickner M, Cheng L, and Zachary IC (2008) Chondroitin sulphate modified Neuropilin-1 is expressed in human tumour cells and modulates 3D invasion in the U87MG human glioblastoma cell line via a p130Cas mediated pathway. EMBO Rep. 9:983-989.

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3. Regulation and Functional Role of Neuropilin-1 Processing in Endothelial Cells

Supervisor(s):
Professor Ian Zachary
Dr Paul Frankel

Department:
Centre for Cardiovascular Biology and Medicine
Research Department of Cardiovascular Medicine

Project outline (5-10 lines):
The VEGF receptor, Neuropilin-1 (NRP1), plays a key role in VEGF signalling and in angiogenesis.. NRP1 can be processed to generate novel membrane-associated carboxy-terminal domain fragments, which are potential regulators of NRP1 and VEGF function. The purpose of this project will be to identify extracellular factors regulating NRP1 processing in endothelial cells, to investigate the role of specific proteases in mediating NRP1 processing, and to examine the functional effects of over-expressing NRP1 carboxy-terminal domain fragments in endothelial cells.

Key reference(s) (max. of 5):

  1. Cheng L Jia H, Löhr M,  Bagherzadeh A, Holmes DIR, Selwood D and Zachary I (2004) Anti-chemorepulsive effects of vascular endothelial growth factor and placental growth factor-2 in dorsal root ganglion neurons are mediated via neuropilin-1 and cyclooxygenase-derived prostanoid production. J Biol Chem. 279:30654-30661.
  2. Holmes DIR and Zachary IC (2008) Vascular Endothelial Growth Factor Regulates Stanniocalcin-1 Expression via Neuropilin-1-dependent Regulaton of KDR and synergism with Fibroblast Growth factor-2. Cell Signal. 20:569-79.
  3. Jia H, Bagherzadeh A, Hartzoulakis B, Jarvis A, Löhr M, Shaikh S, Aqil R, Cheng L, Tickner M, Esposito D, Harris R, Driscoll PC,  Selwood D and Zachary I (2006) Characterisation Of A Bicyclic Peptide Neuropilin-1 (NP-1) Antagonist (EG3287) Reveals Importance Of Vascular Endothelial Growth Factor Exon 8 For NP-1 Binding And Role Of NP-1 In KDR Signalling. J Biol Chem 281:13493-13502.
  4. Pellet-Many C, Paul Frankel P, Jia H, and Zachary IC (2008) Neuropilins: Structure, Function and Role in Disease. Biochem J. 411: 211-226
  5. Frankel P, Pellet-Many C, Lehtolainen P, D'Abaco GM, Tickner M, Cheng L, and Zachary IC (2008) Chondroitin sulphate modified Neuropilin-1 is expressed in human tumour cells and modulates 3D invasion in the U87MG human glioblastoma cell line via a p130Cas mediated pathway. EMBO Rep. 9:983-989.

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4. Cardioprotection by autophagy in ischaemia-reperfusion injury 

Supervisor(s):
Dr Mihaela Moody
Prof Derek Yellon

Department:            
The Hatter Cardiovascular Institute,
University College London

Project outline (5-10 lines):
Recently, autophagy(1) has been proposed as a possible intrinsic cardioprotective mechanism against ischaemia-reperfusion injury.
In this rotation project, the candidate will be exposed to the following:

  • The use of a model of isolated rat hearts (2) to induce ischaemia-reperfusion injury (3) and to reduce this injury using ischaemic preconditioning (IPC) (4). The hearts will also be treated with blockers of autophagy in order to assess the role played by this phenomenon in the protection afforded by IPC. The end point will be the measure of infarct size. In addition, tissue samples will be collected for protein analysis.
  • Western blotting technique (5) will be employed in order to measure the expression of autophagic proteins during preconditioning and during ischaemia-reperfusion injury.

Key reference(s) (max. of 5):

  1. K Nishida, S Kyoi, O Yamaguchi, J Sadoshima and K Otsu  The role of autophagy in the heart. Cell Death and Differentiation (2009) 16, 31–38;
  2. Monika Skrzypiec-Spring, Bartosz Grotthus, Adam Szeląg, Richard Schulz, Isolated heart perfusion according to Langendorff—Still viable in the new millennium. Journal of Pharmacological and Toxicological Methods 55 (2007) 113–126
  3. Hausenloy DJ, Yellon DM New directions for protecting the heart against ischaemia-reperfusion injury: targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway. Cardiovasc Res. 2004 Feb 15;61(3):448-60.
  4. Yellon DM, Downey JM.Preconditioning the myocardium: from cellular physiology to clinical cardiology.Physiol Rev. 2003 Oct;83(4):1113-51. Review.
  5. 4. W. Neal “Western Blotting”: Electrophoretic Transfer of Proteins from Sodium Dodecyl Sulfate-Polyacrylamide Gels to Unmodified Nitrocellulose and Radiographic Detection withAntibody and Radioiodinated Protein Analitical Biochemistry 112, 195-203 (1981

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5. Multiphoton imaging of cardiac responses to ischaemia and reperfusion 

Supervisor(s):
Dr Sean Davidson
Prof Derek Yellon

Department:            
The Hatter Cardiovascular Institute,
University College London

Project outline (5-10 lines):
This project involves the use of multiphoton imaging to visualize the response of the intact heart to ischaemia and reperfusion injury. The advantage of this technique is that serial, high-resolution images can be obtained, either in rats using fluorescent dyes, or in transgenic mice expressing fluorescent, reporter constructs. For example, we have two strains of mice, one expressing a calcium-sensitive fluorescent probe in cardiomyocytes and the other expressing it in the coronary microvasculature. Using these mice we can evaluate the response of the heart to different cardioprotective drugs such as urocortin, leptin or erythropoietin.

Key reference(s) (max. of 5):

  1. Davison SM, Yellon D, Duchen MR. Assessing mitochondrial potential, calcium, and redox state in isolated mammalian cells using confocal microscopy, Methods Mol Biol 372(2007):421-30.
  2. Tallini et al. Imaging cellular signals in the heart in vivo: Cardiac expression of the high-signal Ca2+ indicator GCaMP2, PNAS 103(2006):4753-8.
  3. Davidson SM, Yellon DM. Urocortin: a protective peptide that targets both the myocardium and vasculature, Pharmacol Rep 61(2009):172-82.
  4. Davidson SM, Yellon DM. Dissecting out the mechanism of cardioprotection by endogenous erthyropoietin using genetic engineering, Cardiovasc Res 71(2006):408-410.
  5. Lim SY, Davidson, SM, Hausenloy DJ, Yellon, DM. Preconditioning and postconditioning: the essential role of the mitochondrial permeability transition pore. Cardiovascular Research 75(2007):530-5.

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6. Small animal cardiac MRI to investigate 

Supervisor(s): 
Dr Derek Hausenloy
Prof Derek Yellon

Department:            
The Hatter Cardiovascular Institute,
University College London

Project outline (5-10 lines):
In this rotation project, the candidate will be exposed to the following:

  • The use small animal cardiac MRI to investigate treatment strategies for reducing myocardial infarct size and preventing cardiac failure. Serial imaging over 28 days following a reperfused myocardial infarction will allow us to examine the evolution of the myocardial infarct and the cardiac remodelling which takes place. In addition, it will allow us to assess the efficacy of mechanical and pharmacological treatment strategies for reducing myocardial infarct size and prevent adverse cardiac remodelling.
  • The use of small animal cardiac MRI to visualise apoptosis and inflammation (using iron nanoparticles) to investigate the pathophysiology underlying acute myocardial ischaemia-reperfusion injury and their modification by cardioprotective interventions.

Key reference(s) (max. of 5):

  1. Yellon DM, Hausenloy DJ. Myocardial Reperfusion Injury. New England Journal of Medicine 2007;357:1121-35.
  2. Lim SY, Davidson, SM, Hausenloy DJ, Yellon, DM. Preconditioning and postconditioning: the essential role of the mitochondrial permeability transition pore. Cardiovascular Research 2007:75;530-5.
  3. Hausenloy DJ, Wynne A, Duchen MR, Yellon DM. Transient mitochondrial permeability transition pore opening mediates preconditioning-induced protection. Circulation 2004:109;1714-1717.
  4. Tsang, A, Hausenloy DJ, Mocanu, M, Yellon DM. Postconditioning:- a form of ‘Modified Reperfusion’ protects the myocardium by activating the PI3K-Akt pathway. Circulation Research 2004:95;230-232.
  5. Hausenloy DJ, Maddock HL, Baxter GF, Yellon DM. Inhibiting mitochondrial permeability transition pore opening: a new paradigm in myocardial preconditioning? Cardiovascular Research 2002:55;534-543.

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7. Keeping your mitochondria in shape to protect your heart

Supervisor(s): 
Dr Derek Hausenloy
Prof Derek Yellon

Department:            
The Hatter Cardiovascular Institute,
University College London

Project outline (5-10 lines):
Preliminary data from our laboratory suggests that the shape of mitochondria can influence the susceptibility of the heart to acute ischaemia-reperfusion injury. Specifically, cardiac cells containing elongated interconnected mitochondria were found to be more resistant to simulated ischaemia-reperfusion injury when compared to cardiac cells containing fragmented discrete mitochondria.

In this rotation project, the candidate will investigate whether the changes in mitochondrial calcium, pH, oxidative stress production, which occur during simulated ischaemia-reperfusion injury can explain the cardioprotective effect associated with this particular change in mitochondrial morphology. Laboratory techniques will include: cardiac-cell passaging, DNA plasmid transfection, simulated ischaemia-reperfusion injury, confocal imaging to measure mitochondrial calcium, oxidative stress and pH.

Key reference(s) (max. of 5):

  1. Yellon DM, Hausenloy DJ. Myocardial Reperfusion Injury. New England Journal of Medicine 2007;357:1121-35.
  2. Lim SY, Davidson, SM, Hausenloy DJ, Yellon, DM. Preconditioning and postconditioning: the essential role of the mitochondrial permeability transition pore. Cardiovascular Research 2007:75;530-5.
  3. Hausenloy DJ, Wynne A, Duchen MR, Yellon DM. Transient mitochondrial permeability transition pore opening mediates preconditioning-induced protection. Circulation 2004:109;1714-1717.
  4. Tsang, A, Hausenloy DJ, Mocanu, M, Yellon DM. Postconditioning:- a form of ‘Modified Reperfusion’ protects the myocardium by activating the PI3K-Akt pathway. Circulation Research 2004:95;230-232.
  5. Hausenloy DJ, Maddock HL, Baxter GF, Yellon DM. Inhibiting mitochondrial permeability transition pore opening: a new paradigm in myocardial preconditioning? Cardiovascular Research 2002:55;534-543.

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8. Cardioprotection: Bench to Bedside

Supervisor(s):
Prof Derek Yellon
Dr Derek Hausenloy

Department:            
The Hatter Cardiovascular Institute,
University College London

Project outline (5-10 lines):
Investigating novel treatment strategies to protect human heart muscle from injury.  Using isolated perfusion apparatus will be used to examine the ability of animal and human muscle to withstand severe hypoxia and reoxygenation injury. Molecular biological determinants of injury will be measured; the interrelationship between up-regulation of survival pathways and maintaining the mitochondria in a state that is able to protect the animal as well as human muscle from injury. The above studies are translational and allow the student to undertake a bench to bedside approach to their research.

5 relevant publications:

  1. Jonassen AK, Sack MN, Mjos OD, Yellon DM.Myocardial protection by insulin at reperfusion requires early administration of and is mediated  via Akt and p70s kinase cell survival signalling.  Circ Res 2001; 89:1191-1198.
  2. Hausenloy DJ, Duchen MR, Yellon DMDoes the mitochondrial permeability transition pore have a role in preconditioning?Circulation 2004:109;1714-7
  3. Sivaraman V, Mudalagiri NR, Di Salvo C, Kolvekar S, Hayward M, Yap J, Keogh B, Hausenloy DJ, Yellon DM.Postconditioning protects human atrial muscle through the activation of the RISK pathway.Basic Res Cardiol. 2007 Sep;102(5):453-9. Epub 2007 Jun 5.
  4. Yellon DM, Hausenloy DJMyocardial reperfusion injury.N Engl J Med. 2007 ;357:1121-35. Review
  5. Mudalagiri N, Mocanu M, Di Salvo C, Kolvekar S, Hayward M, Yap J, Keogh B, Yellon DM.Erythropoietin protects the human myocardium against hypoxia/reoxygenation injury via phosphatidylinositol-3 kinase and ERK1/2 activation.Br J Pharmacol. 2008 153:50-6.

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9. Voltage Gated Sodium Channels – Structure and Function

Supervisor(s):
Professor B.A. Wallace

Department:
Crystallography, UCL/Birkbeck Institute of Structural Molecular Biology

Project outline (5-10 lines):
Voltage-gated sodium channels (VGSC) are involved in the generation and propagation of signals in electrically excitable tissues such as muscle and heart. Their activation causes the initial upstroke of the action potential, which then triggers other physiological events leading to muscular contraction and neuronal firing. Many disorders (“channelopathies”) affecting cardiac rhythm have been linked to mutations in human VGSC genes. 

We have recently been able to clone, express, purify a bacterial VGSC, which has high homology and similar functional characteristics to eukaryotic VGSC but has a simpler structure.  This rotation project will span structural biology, chemical biology, bioinformatics and biophysics, as the student would design, clone and express, purifiy, and characterise a mutant bacterial sodium channel protein with altered functional properties.

Key reference(s) (max. of 5):

  1. Cronin, N., O'Reilly, A., Duclohier, H., and Wallace, B.A.  (2003) Binding of the Anticonvulsant Drug Lamotrigine and the Neurotoxin Batrachotoxin to Voltage-gated Sodium Channels Induces Conformational Changes Associated with Block and Steady-State Activation. J. Biol. Chem. 278:10675-10682.
  2. Cronin, N.B., O’Reilly, A., Duclohier, H., and Wallace, B.A. (2005) Effects of Deglycosylation of Sodium Channels on their Structure and Function. Biochemistry 44:441-449.
  3. Lampert, A., O’Reilly, A.O., Dib-Hajj, S.D., Tyrrell, L., Wallace, B.A.*, and Waxman, S.G.* (2008) A pore-blocking hydrophobic motif at the cytoplasmic aperture of the closed-state Nav1.7 channel is disrupted by the erythromelalgia-associated F1449V mutation. J. Biol. Chem. 283:24118-24127. [cover]
  4. Nurani, G., Radford, M., Charalambous, K., O’Reilly, A.O., Cronin, N., Haque, S., and Wallace, B.A. (2008) Tetrameric Bacterial Sodium Channels: Characterisation of Structure, Stability, and Drug Binding. Biochemistry 47:8114-8121.
  5. O’Reilly, A.O., Charalambous, K., Nurani, G., Powl, A.M. and Wallace, B.A. (2008) G219S Mutagenesis as a Means of Stabilising Conformational Flexibility in the Bacterial Sodium Channel NaChBac. Molecular Membrane Biology 25:670-676.

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10. Fine scale Genotype mapping of the SH3B3 gene SNPs in realtionship to LDL-C levels and CHD risk

Supervisor(s):
Steve Humphries, Philippa Talmud, Fotios Drenos

Department:
CVG

Project outline (5-10 lines):
A new candidate gene for CHD risk has been identifed on chromosome 12 by a GWAS study (1). The SH2B3 gene codes for the SH2B ADAPTOR PROTEIN 3.  SH2B3 an adaptor protein that mediates interaction between extracellular receptors and intracellular signalling pathways eg TNF-alpha action on Vascular Smooth Muscle Cells. The Knock-out mouse has profound perturbation of hematopoesis (2).  Several previsous GWAS have found this gene to be associated with tisk of Type 1 Diabetes (WTCCC 2007, Barrett et al 2009), eosinophil number/ Blood Pressure/MI (Gudbjartsson et al 2008),   Celiac Disease  (Hunt et al 2008) and  Blood Pressure and  Hypertension (Levy et al 2009). There is a common  (MAF = 0.5) cSNP (R262W) in SH2B3 that we have not found to be associated with LDL-C in women (p = 7 x 10-5) but not in men in a consortium project containing > 10,000 subjects (Talmud et al submitted)

The current project will be to

  • Identify tagging SNPs for SH2B3 using Hapmap.
  • Design primers for genotyping by Taqman and to genotype 1-2 studies with this SNP
  • Carry out statistical analysis to identify if there is additional variation at this locus, over and above the R262W SNP that is having an effect on LDL-C levels.

Methods learned to include Bioinformatics, Basic genotyping methods and Statistical analysis

Key reference(s) :

  1. Gudbjartsson et al Nature Genetics 2009 41, 324-347
  2. Velazquez et al J Exp Med 2002 195, 1599-1611

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11. The role of adipose tissue cytokines (adipokines) in the link between obesity, depression and cardiovascular disease

Supervisor(s):
Dr. Lena Brydon

Department:
Epidemiology and Public Health

Project outline (5-10 lines):

Obesity is a major risk factor for cardiovascular disease (CVD), and the incidence of depression is significantly elevated in obese individuals and CVD patients. Cytokines, molecules released by adipose tissue and immune cells, play a pivotal role in atherosclerosis. These molecules also signal to the brain through a variety of mechanisms to alter neurotransmitter metabolism and neuroendocrine function, and thereby influence mood. Our group has shown that psychological stress increases circulating cytokine levels in humans, and that these cytokine responses are larger in people with greater adiposity. The project will investigate the association between stress-induced changes in adipose-tissue cytokines (adipokines), obesity, and a range of cardiovascular and psychological outcomes in civil servants from the Whitehall II cohort.

Key reference(s) (max. of 5):

  1. Brydon L., Walker, C., Wawrzyniak, A.J., Whitehead, D., Okamura, H., Yajima, J., Tsuda, A. and Steptoe, A. (2009). Synergistic effects of psychological and immune stressors on inflammatory cytokine and sickness responses in humans, Brain Behaviour and Immunity, 23 (2), 217-224.
  2. Brydon, L., Wright, C. E., O’Donnell, K., Zachary, I., Wardle, J. and Steptoe A. (2008). Stress-induced cytokine responses and central adiposity in young women. International Journal of Obesity (Lond), 32 (3), 443-50.
  3. Brydon, L., O’Donnell, K., Wright, C.E., Wawrzyniak, AJ., Wardle, J. and Steptoe, A.(2008). Circulating leptin and stress-induced cardiovascular activity in humans, Obesity, 16 (12), 2642-2647.
  4. Brydon, L., Edwards, S., Jia, H., Mohamed-Ali, V., Zachary, I., Martin, J.F. and Steptoe, A. (2005). Psychological stress increases interleukin-1b gene expression in human mononuclear cells. Brain, Behavior and Immunity, 19(6), 540-546.
  5. Wright, C. E., Strike, P. C., Brydon, L. and Steptoe, A. (2005). Acute inflammation and negative mood: mediation by cytokine activation. Brain, Behavior and Immunity, 19, 345-350.

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12. Role of nutrition in explaining socioeconomic inequalities in CHD risk factors

Supervisor(s):
Dr Hynek Pikhart and Prof Martin Bobak

Department:
Epidemiology and Public Health

Project outline (5-10 lines):
The HAPIEE (Health, Alcohol and Psychosocial factors in Eastern Europe) study has been set up to investigate the effect of classical and non-conventional risk factors for CHD and other non-communicable diseases in selected countries of CEE and FSU. In this project, student should focus on the role of dietary data on explaining socioeconomic inequalities in CHD risk factors in Russia, Poland, and the Czech Republic, using the data collected during baseline wave of the HAPIEE study.

Key reference(s) (max. of 5):

  1. Peasey A, Bobak M, Kubinova R, Malyutina S, Pajak A, Tamosiunas A, Pikhart H, Nicholson A, Marmot M. Determinants of cardiovascular disease and other non-communicable diseases in Central and Eastern Europe: rationale and design of the HAPIEE study. BMC Public Health. 2006 Oct 18;6:255.

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13. Do salivary cotinine levels distinguish smokers who also report exposure to other people’s smoke, and does this increase their cardiovascular risk?

Supervisor(s):
Dr Jennifer Mindell & Dr Nicola Shelton
Health & Social Surveys Research Group

Department:            
Epidemiology & Public Health

Project outline (5-10 lines):
Both active and passive smoking increase CHD risk.  Quantifying the impact of passive smoking is bedevilled by assessing extent of exposure and confirming personal smoking status.  The Health Survey for England (HSE) is an annual survey of a nationally-representative random sample of the general population, selected anew each year.  It includes an interview and a nurse visit.  Salivary cotinine level is an objective marker for nicotine exposure, discriminating personal tobacco use from passive smoking alone.  HSE data will be used to investigate the impact of self-reported tobacco consumption and of self-reported passive smoking in smokers salivary cotinine levels.
This could lead to work exploring subjective and objective measures of active and passive smoking with cardiovascular hospital admissions.

Key reference(s) (max. of 5):

  1. Craig R, Shelton N (eds). Health Survey for England 2007. Volume 1. Healthy lifestyles: Knowledge, attitudes and behaviour. London: Information Centre, 2008.
  2. Fidler JA, Jarvis MJ, Mindell J, West R. Nicotine intake in cigarette smokers in England: distribution and demographic correlates. Cancer Epidemiol Biomarkers Prev. 2008;17:3331-6.
  3. Jarvis MJ, Fidler J, Mindell J, Feyerabend M, West R. Assessing smoking status in children, adolescents and adults: cotinine cutpoints revisited. Addiction. 2008;103:1553-61.
  4. Mindell J, Wardle H, Nicholson S. The impact of implementation of smokefree legislation in England on location and duration of self-reported exposure to others’ smoke in children and adults. Oral presentation at the 14th world conference on Tobacco or Health, Mumbai, 8-12 March 2009.
  5. Shelton N, Mindell J. Measuring Health in Social Measurement through Social surveys: an applied approach. Aldershot: Ashgate Publishing, due for publication 2009.

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14. Disability and on-going risk factor levels in people with a previous stroke

Supervisor(s):
Dr Jennifer Mindell & Dr Nicola Shelton
Health & Social Surveys Research Group

Department:            
Epidemiology & Public Health

Project outline (5-10 lines):
Cardiovascular mortality has fallen faster than incidence, so more people are living with cardiovascular diseases (CVD).  The Health Survey for England (HSE) is an annual survey of a nationally-representative random sample of the general population, selected anew each year.  HSE 2005 focused on older people and included questions on CVD and on disability, as well as core data (socio-demographic, lifestyle behaviours (smoking, alcohol, fruit and vegetable consumption), self-reported general health, limiting and non-limiting longstanding illness, height, weight, waist and hip circumference, blood pressure, and cholesterol and glycated haemoglobin levels).  This project will explore the level of disability and extent of cardiovascular risk factors of people with a previous stroke, with coronary heart disease, and without CVD.

Key reference(s) (max. of 5):

  1. Constantine R, Mindell J. Volume 1 Chapter 3. Disabilities and incontinence. In Craig R, Mindell J (eds.) Health Survey for England 2005. The health of older people. London: Information Centre, 2007.
  2. Mindell JS, Gatenby R, Cheshire H, Cohen DL. Objective Measures of Physical Function in a Nationally Representative Sample of Non-institutionalised Older Participants in the Health Survey for England. Poster presentation at the British Geriatrics Society, Birmingham, 13-14 November 2008.
  3. Mindell J, Falaschetti E, Volume 1 Chapter 6. Overview. in Craig R, Eds. (ed.) Health Survey for England 2005. The health of older people. London: Information Centre, 2007.
  4. Roth M, Mindell J. Volume 1 Chapter 2. Cardiovascular disease. In Craig R, Mindell J (eds.) Health Survey for England 2006. London: NatCen, 2008.
  5. Shelton N, Mindell J. Measuring Health in Social Measurement through Social surveys: an applied approach. Aldershot: Ashgate Publishing, due for publication 2009.

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15. Changes in social inequalities in obesity and other cardiovascular risk factors over time

Supervisor(s):
Dr Jennifer Mindell & Dr Nicola Shelton
Health & Social Surveys Research Group

Department:
Epidemiology & Public Health

Project outline (5-10 lines):
Smoking has been falling and obesity rising over the past decade.  Both are currently more prevalent in more deprived groups, but have the changes over time been increasing or decreasing socio-economic inequalities?  Using Health Survey for England survey data, mean BMI (body mass index) and blood pressure, prevalence of obesity, smoking, and hypertension, and Framingham cardiovascular risk score will be compared by education level, income quintile, and socio-economic group from 1994 to 2007.  Absolute and relative changes in inequalities will be estimated.

Key reference(s) (max. of 5):

  1. Feri JE, Singh-Manoux A, Kivimäki M, Mindell J, Breeze E, Davey Smith G, Shipley MJ. Cardiovascular risk factors as predictors of 40-year mortality in women and men. Heart. 2009 doi: 10.1136/hrt.2008.164251
  2. Shahab L, Mindell J, Poulter N, West R. Hypertension and its identification among current, past and never smokers in an English population sample. Eur J Cardiovasc Prev Rehab (accepted for publication)
  3. Shelton N, Mindell J. Measuring Health in Social Measurement through Social surveys: an applied approach. Aldershot: Ashgate Publishing, due for publication 2009.
  4. Zaninotto P, Head J, Stamatakis E, Wardle H, Mindell J. Trends in obesity among adults in England from 1993 to 2004 by age and social class and projections of prevalence to 2012. J Epidemiol Community Health. 2009;63:140-6.
  5. Zaninotto P, Mindell J, Hirani V. Prevalence of cardiovascular risk factors among ethnic groups: results from the Health Surveys for England. Atherosclerosis. 2007;195:e48-e57.

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16. Do time trends in cholesterol levels vary by age or by BMI (body mass index) category?

Supervisor(s):
Dr Jennifer Mindell & Dr Nicola Shelton
Health & Social Surveys Research Group

Department:
Epidemiology & Public Health

Project outline (5-10 lines):
Cholesterol levels have fallen in high but not low risk groups in England, through targeted use of lipid-lowering drugs.  In the USA, cholesterol has fallen markedly over time in the oldest two age-groups but a rise in younger age-groups has been hidden by the overall decrease.  Although cardiovascular risk factors remain higher in obese individuals in the USA, the fall in risk factors, such as cholesterol levels, has been higher in obese individuals.

This project will explore changes in Total cholesterol and Total:HDL cholesterol ratio, both including and excluding those on lipid-lowering drugs, by age, sex, and BMI (body mass index) category using  Health Survey for England data.  If time permits, similar analyses can be conducted for changes in blood pressure and control of hypertension.

Key reference(s) (max. of 5):

  1. Falaschetti E, Chaudhury M, Mindell J, Poulter N. Continued improvement in hypertension management in England: Results from the cross-sectional Health Survey for England 2006. Hypertension. 2009;53:480-6.
  2. Gregg FW, Cheng YJ, Cadwell BL et al. Secular trends in cardiovascular disease risk factors according to body mass index in US adults. JAMA. 2005;293:1868-74.
  3. Mindell J, Zaninotto P, Falaschetti E, Poulter N. Hitting a moving target: Changes in hypercholesterolaemia over time in England. (In preparation)
  4. Primatesta P, Poulter N. Levels of dyslipidaemia and improvement in its management in England: results from the Health Survey for England 2003. Clin Endocrinol. 2006;64:292-8.
  5. Shelton N, Mindell J. Measuring Health in Social Measurement through Social surveys: an applied approach. Aldershot: Ashgate Publishing, due for publication 2009.

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17. Do overweight and obese children have high blood pressure?

Supervisor(s):
Dr Nicola Shelton and Dr Jennifer Mindell
Health & Social Surveys Research Group

Department:            
Epidemiology & Public Health

Project outline (5-10 lines):
The prevalence of obesity in children has increased steadily in recent years in England and Scotland. Analyses of US data has found differing levels of impact of the raised BMI on blood pressure in children depending on the study.

This project will explore the relationship between BMI (body mass index) and height adjusted blood pressure in children by age and sex using Health Survey for England and Scottish Health Survey data.  If times permits analysis of additional risk factors will be carried out.

Key reference(s) (max. of 5):

  1. Chaudhury M. Blood Pressure in Bromley C, Sproston K, Shelton N (Eds). The Scottish Health Survey 2003. Vol3 Children Chapter 9. 2005.
  2. Chiolero A, Bovet P, Paradis G, Paccaud F. Has blood pressure increased in Children in Response to the Obesity Epidemic? Pediatrics 2007; 119:544-53
  3. Hansen ML, Gunn PW, Kaelber DC. Underdiagnosis of Hypertension in Children and Adolescents JAMA. 2007;298:874-879.
  4. Sorof J; Daniels S Obesity Hypertension in Children A Problem of Epidemic Proportions Hypertension. 2002;40:441.
  5. Stephenson, J. 2003. Obesity-hypertension link in children? JAMA 289:1774-79

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18. Gender and socioeconomic differences in the onset and diagnosis of cardiovascular disease at old age

Supervisors(s):      
Dr. Edlira Gjonca and Dr Nicola Shelton

Department:           
Epidemiology and Public Health

Project outline (5-10 lines):
The aim of this project is to observe the effect of gender and socio-economic factors at the onset of cardiovascular disease. There is a wide range of work carried out on gender differences in survival and the effect of both socio-economic and behavioural factors. There is also much work on the self-reported health differences and the factors that affect it. However, not much is done on the interplay of these effects and the gender difference in the timing of the onset of chronic diseases, particularly at old age.

This project will use data from the English Longitudinal Study of Ageing. ELSA consisting of a large sample of 12,000 people aged 50 and over (in 2001) who were living at home at the time of interview. Hazard models for the risk of becoming diagnosed will be performed for both sexes, controlling for education, income, wealth, social class, as well as health behaviours.

Key Reference(s) (max. of 5)

  1. Kawano H, Soejima H, Kojima S, Kitagawa A, Ogawa H. Sex differences of risk factors for acute myocardial infarction in Japanese patients. Circ J. 2006; 70(5):513-517.
  2. Coronary heart disease: main cause of death also in the woman. Clear sex differences in diagnosis and therapy. MMW Fortschr Med 2006; 148(5):49.
  3. Cordero A, Alegria E. Sex differences and cardiovascular risk. Heart 2006; 92(2):145-146.
  4. Zaninotto P, Shelton N, Primatesta P. Cardiovascular Disease and Associated Factors in Eds Bromley C, Sproston K, Shelton N. The Scottish Health Survey 2003. Chapter 1 Vol1. 2005.
  5. Nazroo J, Zaninotto P, Gjonça E Mortality and healthy life expectancy. Living in the 21st century: older people in England. The 2006 English Longitudinal Study of Ageing. series, London: Institute for Fiscal Studies. 2008.

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19. Associations between objectively measured sitting and cardiovascular risk factors

Supervisor(s):
Dr Emmanuel Stamatakis and Dr Nicola Shelton
Health & Social Surveys Research Group

Department:            
Epidemiology & Public Health

Project outline (5-10 lines):
An emerging body of evidence suggests that prolonged sedentary behaviour (sitting) is linked to cardiovascular risk regardless of participation in moderate to vigorous physical activity. Available evidence comes primarily from studies that used self-reported and incomplete sedentary time measures making difficult to understand the dose-response of sedentary behaviour and cardiovascular risk outcomes. The 2008 Health Survey for England is the first large scale population survey to collect objective data on physical activity and sedentary behaviour in Europe. 

This aim of this project will be to examine the associations of objectively measured and self reported sedentary time with a range of novel and traditional cardiovascular biological risk factors (blood pressure, BMI/Waist/Hip /glycated haemoglobin/HDL/total cholesterol) while taking into account moderate to vigorous physical activity, cardiovascular medication and other  potential confounders. 

Key reference(s) (max. of 5):

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20. C-reactive protein and physical activity

Supervisor(s):         
Dr Emmanuel Stamatakis and Dr Jennifer Mindell
Health & Social Surveys Research Group

Department:            
Epidemiology & Public Health

Project outline (5-10 lines):
C-reactive protein (CRP) is an indicator of systemic inflammation and an emerging but disputed risk factor for cardiovascular disease. Although exercise has an acute inflammatory effect, regular physical activity has been shown to relate to lower levels of circulating CRP but evidence is inconsistent. Few studies have examined whether age, ethnicity and other known risk factors influence this relationship.  The aim of this project will be to examine the associations between different intensity/volume combinations of physical activity and C-reactive protein and to determine whether these associations vary by age, ethnicity, sex, obesity status, smoking and diabetes.  These questions can be appropriately addressed using Scottish Health Survey and Health Survey for England data. If time permits, this project may be extended to include cardiovascular mortality outcomes.

Key reference(s) (max. of 5):

  1. Hamer M, Stamatakis E. Physical activity and risk of CVD Events: inflammatory and metabolic mechanisms. Medicine and Science in Sports and Exercise 2009; 41:1206-1211
  2. Kasapis C, Thompson PD. The effects of physical activity on serum C-reactive protein and inflammatory markers: a systematic review. J Am Coll Cardiol 2005;45:1563–9.
  3. Majka DS, Chang RW, Vu THT, Palmas W, Geffken DF, Ouyang P, et al. Physical Activity and High-Sensitivity C-Reactive Protein The Multi-Ethnic Study of Atherosclerosis. American Journal of Preventive Medicine 2009;36:56-62.
  4. Albert MA, Glynn RJ, Ridker PM. Effect of physical activity on serum C-reactive protein. American Journal of Cardiology 2004;93:221-225.
  5. Hamer M, Chida Y, Stamatakis E. Utility of C-reactive Protein for Cardiovascular Risk Stratification across Three Age  Groups in Subjects without Existing Cardiovascular Diseases

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21. Risk of specific coronary phenotypes in large populations

Supervisor(s):         
Professor Harry Hemingway

Department:           
Epidemiology and public health

Project outline (5-10 lines):
Background: Epidemiological understanding of coronary disease is based on broad aggregates of myocardial infarction, coronary death or both.   Previous studies have lacked the statistical size, and clinical resolution to distinguish different chronic and acute coronary syndromes, which are known to differ in underlying vascular biology, and prognosis.

Methods:  The main dataset will be an internationally unique linkage between the complete primary care record (about 2 million people in the General Practice Research Database, www.gprd.com) and the national registry of acute coronary syndromes (the Myocardial Infarction National Audit Project (www.rcplondon.ac.uk). 

Training experience: working with a team of cardiologists, general practitioners, statisticians and epidemiologists; strengths and weaknesses of electronic health records for research; literature review; statistical analysis.

Key reference(s) (max. of 5):

  1. Hemingway H, Langenberg C, Damant J, Frost C, Pyörälä K, Barrett-Connor E. Prevalence of angina in women versus men: a systematic review and meta-analysis of international variations across 31 countries. Circulation. 2008 Mar25;117(12):1526-36. Epub 2008 Mar 17. PubMed PMID: 18347213.
  2. Timmis AD, Feder G, Hemingway H. Prognosis of stable angina pectoris: why we need larger population studies with higher endpoint resolution. Heart. 2007Jul;93(7):786-91. Epub 2006 Sep 4. PubMed PMID: 16952966.
  3. Hemingway H, McCallum A, Shipley M, Manderbacka K, Martikainen P, Keskimäki I. Incidence and prognostic implications of stable angina pectoris among women and men. JAMA. 2006 Mar 22;295(12):1404-11. Erratum in: JAMA. 2006 Jun 7;295(21):2482. PubMed PMID: 16551712.

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22. Using genetic studies in populations as naturally randomised trials for drug development

Supervisor(s):
Professor Aroon Hingorani
Dr Juan Pablo Casas
Professor Steve Humphries
Professor Philippa Talmud
Dr Meena Kumari          

Department:
Medicine and Epidemiology

Project outline (5-10 lines):
In the last 5 years, whole genome association studies involving large collaborations with many thousand of samples from disease case collections and highly-phenotyped populations have led to the discovery of many hundreds of genes contributing to individual differences in susceptibility to common human disorders as well as disease-relevant biomarkers and traits. We have developed new methods for applying these advances in complex disease genetics for drug development exploiting the concept that genetic studies in human populations have properties akin to the randomized controlled clinical trials, the pivotal investigation when evaluating a new drug and its target. This new method will be applied to testing the validity of a range of high priority drug targets in diabetes and heart disease capitalizing on the large highly phenotyped population studies at UCL (n=25,000) as well as through established national and international collaborations. (See also: http://www.ucl.ac.uk/genetic-epidemiology/).

Key reference(s) (max. of 5):

  1. Drenos F, Talmud PJ, Casas JP, Smeeth L, Palmen J, Humphries SE, Hingorani AD. Integrated associations of genotypes with multiple blood biomarkers linked to coronary heart disease risk. Hum Mol Genet. 2009 Jun 15;18(12):2305-16. Epub 2009 Mar 31. PubMed PMID: 19336475; PubMed Central PMCID: PMC2685759.
  2. Kivimäki M, Lawlor DA, Smith GD, Kumari M, Donald A, Britton A, Casas JP, Shah T, Brunner E, Timpson NJ, Halcox JP, Miller MA, Humphries SE, Deanfield J, Marmot MG, Hingorani AD. Does high C-reactive protein concentration increase atherosclerosis? The Whitehall II Study. PLoS One. 2008 Aug 20;3(8):e3013. PubMed PMID: 18714381; PubMed Central PMCID: PMC2507732.
  3. Verzilli C, Shah T, Casas JP, Chapman J, Sandhu M, Debenham SL, Boekholdt MS, Khaw KT, Wareham NJ, Judson R, Benjamin EJ, Kathiresan S, Larson MG, Rong J, Sofat R, Humphries SE, Smeeth L, Cavalleri G, Whittaker JC, Hingorani AD. Bayesian meta-analysis of genetic association studies with different sets of markers. Am J Hum Genet. 2008 Apr;82(4):859-72. PubMed PMID: 18394581; PubMed Central PMCID: PMC2665011.
  4. Casas JP, Shah T, Cooper J, Hawe E, McMahon AD, Gaffney D, Packard CJ, O'Reilly DS, Juhan-Vague I, Yudkin JS, Tremoli E, Margaglione M, Di Minno G, Hamsten A, Kooistra T, Stephens JW, Hurel SJ, Livingstone S, Colhoun HM, Miller GJ, Bautista LE, Meade T, Sattar N, Humphries SE, Hingorani AD. Insight into the nature of the CRP-coronary event association using Mendelian randomization. Int J Epidemiol. 2006 Aug;35(4):922-31. Epub 2006 Mar 24. PubMed PMID: 16565153.
  5. Hingorani A, Humphries S. Nature's randomised trials. Lancet. 2005 Dec 3;366(9501):1906-8. PubMed PMID: 16325682.

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23. RNA Interference of E2F Transcription Factors as a Potential Therapeutic Modality for Neointimal Hyperplasia

Supervisor(s):
Stephen Hart, Jean McEwan

Department:
Wolfson Centre for Gene Therapy of Child Hood Disease, UCL Institute of Child Health

Project outline (5-10 lines):
Neointimal hyperplasia (IH) involves the proliferation and migration of vascular smooth muscle cells in veins and arteries. Excessive IH is often associated with stenosis of vein grafts after bypass surgery and of restenosis of coronary arteries after balloon angioplasty. In this project we will transfect smooth muscle cells with siRNAs that target specific members of the E2F family of transcription factors which regulate a number of genes, such as c-myc and c-myb, which are actively involved in cell replication. Efficacy will be assessed by cell proliferation and migration assays, as well as E2F, c-myc and c-Myb expression analysis by quantitative RT-PCR for the mRNA transcripts and Western analysis for the proteins.

Key reference(s) (max. of 5):

  1. Attwooll C, Lazzerini Denchi E, Helin K. The E2F family: specific functions and overlapping interests. Embo J 2004; 23: 4709-4716.
  2. Irvine SA et al. Receptor-targeted nanocomplexes optimized for gene transfer to primary vascular cells and explant cultures of rabbit aorta. Mol Ther 2008; 16: 508-515.
  3. Meng QH, Jamal W, Hart SL, McEwan JR. Application to Vascular Adventitia of a Nonviral Vector for TIMP-1 Gene Therapy to Prevent Intimal Hyperplasia. Hum Gene Ther 2006.
  4. Ehsan A, Mann MJ, Dell'Acqua G, Dzau VJ. Long-term stabilization of vein graft wall architecture and prolonged resistance to experimental atherosclerosis after E2F decoy oligonucleotide gene therapy. J Thorac Cardiovasc Surg 2001; 121: 714-722.
  5. Dollery CM et al. Expression of tissue inhibitor of matrix metalloproteinases 1 by use of an adenoviral vector inhibits smooth muscle cell migration and reduces neointimal hyperplasia in the rat model of vascular balloon injury. Circulation 1999; 99: 3199-3205.

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24. Analysing the role of transcriptional regulator, Brn-3b/POU4F2, in developmental and pathological hypertrophy

Supervisor(s):
Dr Vishwanie Budhram-Mahadeo and Dr Richard Heads

Department:
Medical Molecular Biology Unit, UCL Institute of Child Health

Project outline (5-10 lines):
Myocardial hypertrophy can alter heart function and if chronic, can lead to heart failure. The proliferation-associated Brn-3b transcription factor may have a role in mediating such changes because its over-expression results in development of hyperplastic heart valves and ventricles whereas Brn-3b KO hearts show attenuated responses to hyper-trophic stimuli. Moreover, Brn-3b is, itself, activated by MAPK/ERK pathway, which is a key signalling pathway involved in mediating cardiac hypertrophy. We will therefore analyse roles for Brn-3b during developmental and pathological hypertrophy and determine if changing Brn-3b expression alters cellular responses to hypertrophic stimuli.

Outline for Rotation project (3-4 months):

  1. Culture primary cardiac myocytes and treat with different hypertrophic stimuli.
  2.  Analyse Brn-3b and known proliferation associated target genes, e.g., cyclinD1/ CDK4 in treated and untreated cells, using molecular approaches e.g. quantitative RT-PCR (for mRNA) and immunoblotting (protein).
  3. Undertake co-immunostaining studies to analyse Brn-3b with hypertrophic markers in treated and untreated cells.
  4. Time permitting, use RNA interference to reduce Brn-3b in cultured myocytes and test for response to hypertrophic stimuli, to confirm its role in these effects.

These results can lead to subsequent studies to:
- analyse response of adult Brn-3b KO hearts to hypertrophic stimulus in-vivo, by implanting slow-release pumps with hypertrophic drug e.g. angiotensin II and compare with untreated KO hearts or hearts from untreated wild type (WT) animals. Undertake functional and molecular/cellular analysis of treated and untreated hearts from WT & KO animals. 
- Generate transgenic mice over-expressing Brn-3b (commercially) and analyse for developmental hypertrophy during embryogenesis or response of mature myocytes to hypertrophic stimulus using in-vivo and in vitro studies.
- Undertake Microarray analysis to identify genes that are differentially regulated between Brn-3b KO hearts, transgenic hearts over-expressing Brn-3b, compared with normal controls. Validate specific target genes and analyse role in hypertrophy.

Key reference(s) (max. of 5):

  1. Heineke, J. and Molkentin J.D. 2006. Regulation of cardiac hypertrophy by intracellular signalling pathways. Nat. Rev. Mol. Cell Biol. 7:589-600.
  2. Molkentin, J.D. and Olson EN. 1997. GATA4: a novel transcriptional regulator of cardiac hypertrophy? Circulation 96:3833-3835.
  3. Braz, J. C., O. F. Bueno, Q. Liang, B. J. Wilkins, Y. S. Dai, S. Parsons, J. Braunwart, B. J. Glascock, R. Klevitsky, T. F. Kimball, T. E. Hewett, and J. D. Molkentin. 2003. Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling. J. Clin. Invest 111:1475-1486.
  4. Farooqui-Kabir S R; Diss J K J; Henderson D; Marber MS; Latchman D S; Budhram-Mahadeo V; Heads RJ (2008) Cardiac expression of Brn-3a and Brn-3b POU transcription factors and regulation of Hsp27 gene expression. Cell Stress & Chaperones 2008;13(3):297-12.
  5. Budhram-Mahadeo VS, Irshad, S; Bowen S, Lee S, Tonini GP and Latchman DS (2008) Proliferation-associated Brn-3b transcription factor can activate cyclin D1 expression in neuroblastoma and breast cancer cells Oncogene. Jan 3;27(1):145-54

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25. The regulation of cardiac and vascular smooth muscle cell excitability by ion channels and G-proteins

Supervisor(s): 
Andrew Tinker

Department:
Medicine

Project outline (5-10 lines):
We are interested in the molecular mechanisms of how ion channels in particular K+ channels in the cardiovascular system are regulated by cell signalling pathways and how this might underlie abnormal heart rhythm and aberrant vascular reactivity. Specific topics include (i) the molecular identity of vascular ATP-sensitive K+ channels and their role in the regulation of vascular tone (ii) the molecular mechanisms by which acetylcholine slows the heart rate (iii) how hereditary mutations in ion channel and other genes can lead to cardiac disease (iv)  how autonomic control precipitates cardiac arrhythmia. We study these questions at a number of different levels including in-vitro systems such as cell lines and in-vivo in mouse models and use a range of techniques including molecular biology, biochemistry, cell imaging, single cell electrophysiology and a variety of in-vivo physiological assays. Rotations could be offered in any of these areas and training shaped both intellectually and technically to the student’s interests. I am happy to discuss any rotation project in greater and more specific detail.

Key reference(s) (max. of 5):

  1. ZUBERI, Z., BIRNBAUMER, L. & TINKER, A. (2008). The role of inhibitory heterotrimeric G-proteins in the control of in-vivo heart rate dynamics. American Journal of Physiology (Regul Integr Comp Physiol). 295, R1822-30
  2. NOBLES, M., BENIANS, A. & TINKER, A. (2005). Heterotrimeric G proteins precouple with G protein-coupled receptors in living cells. Proceedings of the National Academy of Sciences (USA) (via track II) 102, 6239-6244
  3. WILSON, A.J., QUINN, K.V., GRAVES, F.M., BITNER-GLINDZICZ, M. & TINKER, A. (2005) Abnormal KCNQ1 trafficking influences disease pathogenesis in hereditary long QT syndromes (LQT1). Cardiovascular Research 67, 476-86.
  4. BENIANS, A., NOBLES, M., HOSNY, S. & TINKER, A. (2005). Regulators of G-protein signalling form a quaternary complex with the agonist, receptor and G-protein: a novel explanation for the acceleration of signalling activation kinetics. Journal of Biological Chemistry 280, 13383-13394.
  5. QUINN, K., GIBLIN, J., & TINKER, A. (2004) A multi-site phosphorylation mechanism for protein kinase A activation of the smooth muscle ATP-sensitive K+ channel. Circulation Research 94, 1359-1366.

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26. PPARg as a therapeutic target for prostacyclin analogues in proliferative lung disease

Supervisor(s):
Professor Lucie Clapp and Professor David Abraham

Department:
Medicine (Rayne & Royal Free)

Project outline (5-10 lines):
The ligand-activated transcription factor PPARγ is an important regulator of cell growth, cell differentiation, inflammation and apoptosis (Nisbet et al., 2007). Studies have also established a critical role for PPARγ in the development of pulmonary hypertension (Hansmann et al., 2008) and in the fibrotic disease, systemic sclerosis (Kapoor et al, 2009). Recently we have shown that prostacyclin analogues, which are used clinically to treat these two conditions, can activate PPARγ in a HEK-293 cell line and contribute to the antiproliferative responses of these agents (Clapp et al, 2002; Falcetti et al, 2007). Using mice where PPARγ has been conditionally deleted specifically in fibroblasts, we now wish to test the hypothesis that PPARγ contributes to the antifibrotic and antiproliferative effects of prostacyclin analogues in lung fibroblasts.  

Key reference(s) (max. of 5):

  1. Nisbet RE, Sutliff RL, Hart CM (2007). The role of peroxisome proliferator-activated receptors in pulmonary vascular disease. PPAR Res 2007: 18797.
  2. Hansmann G, de JP, V, Alastalo TP, Alvira CM, Guignabert C, Bekker JM et al. (2008). An antiproliferative BMP-2/PPARgamma/apoE axis in human and murine SMCs and its role in pulmonary hypertension. J Clin Invest 118: 1846-1857.
  3. Kapoor M, McCann M, Liu S, Huh K, Denton CP, Abraham DJ, Leask A (2009). Loss of peroxisome proliferator–activated receptor in mouse fibroblasts results in increased susceptibility to bleomycin-induced skin fibrosis.  Arthritis Rheum. 60: In press
  4. Clapp LH, Finney PA, Turcato S, Tran S, Rubin LJ, Tinker A (2002). Differential effects of stable prostacyclin analogues on smooth muscle proliferation and cyclic AMP generation in human pulmonary artery. Am J Respir Cell Molec Biol 26: 194-201.
  5. Falcetti E, Flavell DM, Staels B, Tinker A, Haworth SG, Clapp LH (2007). IP receptor-dependent activation of PPARg by stable prostacyclin analogues. Biochem Biophys Res Commun 360: 821-827.

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27. Phosphorylation of the nuclear receptor LXRa induced by agonists with different metabolic actions

Supervisor(s):
Dr. Inés Pineda-Torra

Department:
Division of Medicine, Centre for Clinical Pharmacology

Project outline (5-10 lines):
Liver X receptors (LXR) are lipid-activated transcription factors that can activate or repress gene transcription in a ligand- and gene-specific fashion [1]. They are currently considered important drug targets for the treatment of metabolic as well as inflammatory diseases like atherosclerosis. A number of synthetic LXR ligands have been developed including T0901317 and GW3965. These compounds are structurally distinct and present differences in their biological activities although they both reduce atherosclerosis progression in different mouse models. These beneficial effects, however, are observed despite a deleterious induction of plasma triglyceride levels. Recently, the synthetic oxysterol DMHCA showed anti-atherogenic effects with no observed hypertriglyceridemia [2]. Our studies indicate that LXRa phosphorylation is ligand-induced by T0901317, which results in the selective regulation of target gene expression [3]. This project will aim to examine LXRa phosphorylation status in macrophage and liver cell lines in the presence of GW3965 and DMHCA ligands using phospho-specific antibodies against phosphorylated LXRa. In addition, the effects of LXRa phosphorylation site- mutations on its target gene expression in these cells will be examined.

Key reference(s) (max. of 5):

  1. Fievet, C., Staels, B., Biochem Pharmacol 2009, 77, 1316-1327.
  2. Kratzer, A., Buchebner, M., Pfeifer, T., Becker, T. M., et al., J Lipid Res 2009, 50, 312-326.
  3. Torra, I. P., Ismaili, N., Feig, J. E., Xu, C. F., et al., Mol Cell Biol 2008, 28, 2626-2636.

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28. Identifying the functional SNPs in the CELSR2/SORT1 locus, associated with differences in LDL cholesterol levels

Supervisor(s):
Philippa Talmud and Andrew Smith

Department:
Medicine

Project outline (5-10 lines):
We have developed a Multiplexed competitor EMSA, to screen for ~70 transcription factor consensus sequences in cocktails of 10 at a time. The proposal is for the student to look at the recently identified CELSR2/SORT locus, associated with LDL cholesterol levels and to and identify the functional variant responsible for this association, using this methodology and luciferase assays.

Key reference(s) (max. of 5):

  1. Smith,A.J., and Humphries,S.E. (2009). Characterization of DNA-binding proteins using multiplexed competitor EMSA. J. Mol. Biol. 385, 714-717
  2. Sandhu,M.S., Waterworth,D.M., Debenham,S.L., Wheeler,E., Papadakis,K., Zhao,J.H., Song,K., Yuan,X., Johnson,T., Ashford,A. et al. (2008). LDL-cholesterol concentrations: a genome -wide association study. Lancet 371, 483-491
  3. Willer,C.J., Sanna,S., Jackson,A.U., Scuteri,A., Bonnycastle,L.L., Clarke,R., Heath,S.C., Timpson,N.J., Najjar,S.S., Stringham,H.M. et al. (2008). Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat. Genet. 40, 161-169

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29. Regulation of HIF-mediated angiogenesis by HDM2

Supervisor(s):
Dr Margaret Ashcroft (primary) and Prof Patrick Maxwell (secondary), Centre for Cell Signalling and Molecular Genetics

Department:
Metabolism and Experimental Therapeutics

Project outline (5-10 lines):
Hypoxia inducible factors (HIFs) are transcription factors that play a key role in angiogenesis. HIF is a dimeric complex consisting of α and β subunits. HIF activity is dependent on the availability of HIF-α which is tightly regulated. Deregulation of HIF-α occurs in many human diseases including cardiovascular disease and cancer.

Recently, we have shown that the E3 ligase HDM2 is a novel positive regulator of HIF and mediates the differential regulation of HIF angiogenic targets (VEGF, PAI-1, and ET-1) via an unknown mechanism involving ERK1/2 signalling. The PhD project will broadly aim to 1) examine the cross talk between HDM2 and the regulation of angiogenic processes in the presence and absence of HIF-α and 2) identify key mechanisms that govern HIF-mediated angiogenesis via the ERK1/2 pathway and HDM2.

Key reference(s) (max. of 5):

  1. Carroll V and Ashcroft M. (2008) Regulation of angiogenic factors by HDM2 in renal cell carcinoma. Cancer Research 15;68(2):545-52.
  2. Sutton KM, Hayat S, Chau NM, Cook S, Pouyssegur J, Ahmed A, Perusinghe N, Le Floch R, Yang J and Ashcroft M. (2007) Selective inhibition of MEK1/2 reveals a differential requirement for ERK1/2 signalling in the regulation of HIF-1 in response to hypoxia and IGF-1. Oncogene 26(27):3920-9.
  3. Bárdos JI, Chau N-M, Ashcroft M. (2004) Growth factor-mediated induction of HDM2 positively regulates HIF-1α expression. Mol Cell Biol 24 (7): 2905-2914.Ashcroft M, Ludwig RL, Woods DB, Copeland TD, Weber O, MacRae EJ, Vousden KH. (2002) Phosphorylation of HDM2 by Akt. Oncogene, 21: 1955-1962.
  4. Ashcroft M, Yoichi T, Vousden KH. (2000) Stress Signals Utilize Multiple Pathways to Stabilize p53. Mol Cell Biol 20(9):3224-3233.
  5. Lohrum MAE, Ashcroft M, Kubbutat MHG, Vousden KH. (2000) Identification of a Cryptic Nucleolar Localization Signal in MDM2. Nature Cell Biol 2:179-181.

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30. Validating embryonic/cardiac downstream targets of Thymosin b4

Supervisor(s):
Prof Paul Riley & Dr Nicola Smart

Department:
UCL-Institute of Child Health (Molecular Medicine Unit)

Project outline (5-10 lines):
Thymosin b4 (Tb4) is essential for epicardium-derived coronary vessel development and activation of the adult epicardium to contribute vascular precursors for neovascularisation1.  We have generated microarray data from wild type versus Tb4-null embryos and adult wild type versus Tb4-null hearts and have a list of candidate downstream Tb4 target genes.  This rotation project will validate one or two selected candidates using qRT-PCR, northern/western analyses and in situ hybridisation/immunostaining on embryonic/adult heart sections, thus establishing the basis for further functional studies to define the downstream effector(s) of Tb4 function.

Key reference(s) (max. of 5)

  1. Smart, N. et al. Thymosin beta4 induces adult epicardial progenitor mobilization and neovascularization. Nature 445, 177-182 (2007).

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31. Optimising microsphere uptake/RNAi knockdown in embryonic and adult epicardium-derived progenitor cells

Supervisor(s):
Professor Paul Riley & Dr Sveva Bollini

Department:
UCL-Institute of Child Health (Molecular Medicine Unit)

Project outline (5-10 lines):
The epicardium, the outer mesothelial layer of the heart, contributes vascular endothelial cells and smooth muscle cells to the developing coronary vasculature1.  More recently activated adult epicardium-derived progenitor cells have been shown by our group to have the potential for neovascular- based repair following ischaemic injury (“heart attack”)2.  We are now adopting an approach to target potential key signalling molecules which may underpin the activation of adult EPDCs using a novel microsphere-based delivery of shRNA, in collaboration with Dr Joshua Brickman at the ISCR Edinburgh.   This rotation project will determine the optimum size of microsphere for uptake by EPDCs using fluorescently-tagged spheres and will move towards testing a candidate shRNA directed against one of the following critical foetal epicardium genes such as Tbx18, Raldh2 or Wt-13.  This project will form the basis of a larger scale shRNA screen against a panel of candidate genes identified as up-regulated during adult zebrafish heart regeneration4 which is itself underpinned by organ wide activation of the epicardium.

Key reference(s) (max. of 5):

  1. Luttun, A. & Carmeliet, P. De novo vasculogenesis in the heart. Cardiovasc. Res. 58, 378-389 (2003).
  2. Smart, N. et al. Thymosin beta4 induces adult epicardial progenitor mobilization and neovascularization. Nature 445, 177-182 (2007).
  3. Smart, N., Dube, K. N. & Riley, P. R. Coronary vessel development and insight towards neovascular therapy. Int. J. Exp. Pathol. 90, 262-283 (2009).
  4. Lien, C. L., Schebesta, M., Makino, S., Weber, G. J. & Keating, M. T. Gene Expression Analysis of Zebrafish Heart Regeneration. PLoS. Biol. 4, (2006).

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32. Investigating the role of Prox1 in the cardiac lymphatic vasculature

Supervisor(s):
Professor Paul Riley & Dr Catherine Risebro

Department:
UCL-Institute of Child Health (Molecular Medicine Unit)

Project outline (5-10 lines):
Prox1 is a homeodomain transcription factor essential for development of the embryonic lymphatic vasculature1 and we have recently revealed an additional role for Prox1 in maintaining cardiomyocyte ultrastructure and growth in the developing heart2.  We would now like to investigate whether Prox1 is required for the development of the cardiac lymphatic system as an important source of fluid/lipid transport in the maturing heart.  We will characterise the lymphatic vasculature within the developing, neonatal and mature mouse heart and determine expression of Prox1 in the cardiac lymphatics by co-immunostaining with the lymphatic molecular marker LYVE1.  This rotation project will form the basis of future studies examining a putative lymphatic phenotype following loss of Prox1 function in the heart via our existing Cre-Lox mouse models. 

Key reference(s) (max. of 5):

  1. Wigle, J. T. & Oliver, G. Prox1 function is required for the development of the murine lymphatic system. Cell 98, 769-778 (1999).
  2. Risebro, C. A. et al. Prox1 maintains muscle structure and growth in the developing heart. Development 136, 495-505 (2009).

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33. Tissue specific requirements for the chromatin remodeler Chd7 during heart development

Supervisor(s): 
Prof Peter Scambler

Department: 
UCL-ICH (Molecular Medicine Unit)

Project outline (5-10 lines):
The gene encoding the chromatin remodelling protein Chd7 is haploinsufficient in the CHARGE association, a multisystem birth defect including cardiovascular malformation.  Conditional rescue of a gene-trap allele reveals that Chd7 is required for great vessel morphogenesis.  The project will involve analysis of new conditional gene expression rescue experiments.  Drivers for the second heart field and the pharyngeal endoderm are available.  Recent data demonstrate a role for Chd7 in controlling stem/progenitor cell proliferation in olfactory epithelia.  Experiments will be aimed at determining the phenotype of conditionally rescued embryos, with a particular view towards cellular differentiation, proliferation and apoptosis. 

Key reference(s) (max. of 5):

  1. Vissers,L.E., van Ravenswaaij,C.M., Admiraal,R., Hurst,J.A., de Vries,B.B., Janssen,I.M., van,d., V, Huys,E.H., De Jong,P.J., Hamel,B.C., Schoenmakers,E.F., Brunner,H.G., Veltman,J.A., and van Kessel,A.G. (2004). Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat. Genet. 36, 955-957.
  2. Schnetz,M.P., Bartels,C.F., Shastri,K., Balasubramanian,D., Zentner,G.E., Balaji,R., Zhang,X., Song,L., Wang,Z., Laframboise,T., Crawford,G.E., and Scacheri,P.C. (2009). Genomic distribution of CHD7 on chromatin tracks H3K4 methylation patterns. Genome Res. 19, 590-601.
  3. Randall,V., McCue,K., Roberts,C., Kyriakopoulou,V., Beddow,S., Barrett,A.N., Vitelli,V., Prescott,K., Shaw-Smith,C., Devriendt,K., Bosman,E., Steffes,G., Steel,K.P., Simrick,S., Basson,M.A., Illingworth,E. and Scambler,P.  Great vessel development requires biallelic expression of Chd7 and Tbx1 in pharyngeal ectoderm.  Journal of Clinical Investigation, in press.

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34. Developing novel models to study embryonic pharyngeal surface ectoderm as a signalling centre

Supervisor(s): 
Prof Peter Scambler, Dr. Karen McCue

Department: 
UCL-ICH (Molecular medicine Unit)

Project outline (5-10 lines):
The embryonic pharyngeal ectoderm is an important signalling centre for directing the cardiac neural crest and its contribution to development of the great vessels.  GFP- expressing transgenics will be used to characterise gene expression profiles in animal models of either DiGeorge or CHARGE syndrome in order to investigate events downstream of mutation in the relevant genes, Tbx1 and Chd7 respectively.  The project will involve flow-cytometry and array based and/or Q-RTPCR based analysis of gene expression during the relevant periods of mouse embryogenesis.  This will be followed up by molecular analysis of mutant embryos using in situ and immunohistochemical methods.

Key reference(s) (max. of 5):

  1. Ivins,S., Lammerts van Beuren,K., Roberts,C., James,C., Lindsay,E., Baldini,A., Ataliotis,P., and Scambler,P.J. (2005). Microarray analysis detects differentially expressed genes in the pharyngeal region of mice lacking Tbx1. Dev. Biol. 285, 554-569.
  2. Genomic and Transcriptomic Approaches to Pathways affected in DiGeorge Syndrome.  PhD thesis.  Kelly Lammerts van Beuren, London 2007.
  3. Two preprints of papers in press from the host lab. (Development, and Journal of Clinical Investigation) will be made available

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35. Protein interactions of Hic2

Supervisor(s): 
Prof Peter Scambler

Department:
UCL-ICH (Molecular Medicine Unit)

Project outline (5-10 lines):
We have recently shown that Hic2  (Hypermethylated in Cancer - 2) is deleted in humans with atypical 22q11 deletions and DiGeorge syndrome.  A mouse model shows ventricular septal defects in heterozygotes (i.e. there is haploinsufficiency) and homozygotes die very early.  Hic2 is closely similar to Hic1 at the protein level, with one protein interaction domain 100% conserved.  The project will begin to test the hypothesis that functional interactions are conserved using in vitro protein interaction assays and cell transfections.  In particular, the possibility that Hic2 suppresses canonical Wnt signalling by sequestering Tcf will be explored.  Thus, novel mechanisms underlying cardiovascular morphogenesis will be explored.

Key reference(s) (max. of 5):

  1. Deltour,S., Pinte,S., Guerardel,C., Wasylyk,B., and Leprince,D. (2002). The human candidate tumor suppressor gene HIC1 recruits CtBP through a degenerate GLDLSKK motif. Mol. Cell Biol. 22, 4890-4901.
  2. Chen,W.Y., Wang,D.H., Yen,R.C., Luo,J., Gu,W., and Baylin,S.B. (2005). Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Cell. 123, 437-448.
  3. Valenta,T., Lukas,J., Doubravska,L., Fafilek,B., and Korinek,V. (2006). HIC1 attenuates Wnt signaling by recruitment of TCF-4 and beta-catenin to the nuclear bodies. EMBO J. 25, 2326-2337.
  4. Genomic and Transcriptomic Approaches to Pathways affected in DiGeorge Syndrome.  PhD thesis.  Kelly Lammerts van Beuren, London 2007.

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36. Investigation of a novel protein that modifies TGF-β signalling and promotes retinal angiogenesis

Supervisor(s):
Professor John Greenwood
Professor Stephen Moss

Department:
Department of Cell Biology, UCL Institute of Ophthalmology

Project outline (5-10 lines):
Retinal angiogenesis, caused by diseases such as diabetes and age-related macular degeneration, represents a major cause of blindness in industrialised countries. Using differential gene expression analysis we have identified a potentially important and novel regulator of angiogenesis in the retina. Preliminary studies on the protein have revealed that it regulates TGF-β signalling and promotes angiogenesis in vitro. In this project we will investigate in further detail the role of this protein in modifying the TGF-β signalling pathway in endothelial cells and its effect on in vitro models of angiogenesis.

Key reference(s) (max. of 5):

  1. Angiogenesis, TGF-β signalling, retina, diabetes

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37. Novel roles for VEGF and neuropilin signalling in physiological angiogenesis and the control of cardiovascular tone

Supervisor(s):
Dr C Ruhrberg

Department:
UCL Institute of Ophthalmology

Project outline (5-10 lines):
The Ruhrberg lab elucidates novel roles for VEGF and neuropilin signalling in physiological angiogenesis and the control of cardiovascular tone. One rotation project will address how losing neuropilin signalling affects the sympathetic innervation of the heart. An alternative project will investigate the role of VEGF and neuropilin in smooth muscle differentiation and remodelling of the great vessels.

Key reference(s) (max. of 5):

  1. Schwarz Q, Maden C, Vieira JM, Ruhrberg C. (2009). Neuropilin 1 signalling guides neural crest cells to coordinate pathway choice with cell specification. Proc Natl Acad Sci USA106:6164-69.
  2. Schwarz Q, Vieira JM, Howard B, Eickholt B and Ruhrberg C (2008). Neuropilin 1 and neuropilin 2 control cranial gangliogenesis and axon guidance through neural crest cells. Development135:1605-1613.
  3. Vieira JM, Schwarz Q and Ruhrberg C (2007). Selective requirements for neuropilin ligands in neurovascular development. Development134 (10): 1833-1843.
  4. Schwarz Q, Gu C, Fujisawa H, Sabelko K, Gertsenstei, M, Nagy A, Taniguchi M, Kolodkin AL, Ginty DD, Shima DT and Ruhrberg C (2004). Vascular endothelial growth factor controls neuronal migration and cooperates with Sema3A to pattern distinct compartments of the facial nerve. Genes & Development18:2822-2834.
  5. Ruhrberg C, Gerhardt H, Golding M, Watson R, Ioannidou S, Fujisawa H, Betsholtz C and Shima DT (2002). Spatially-restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching. Genes & Development16: 2684-2698.

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38. Vascular endothelial growth factor (VEGF) signalling in microvascular endothelial cells

Supervisor(s):
Dr Patric Turowski

Department:
UCL Institute of Ophthalmology

Project outline (5-10 lines):
Vascular endothelial growth factor (VEGF) triggers the angiogenic programme of endothelial cells and also potently induces vascular permeability and oedema.  We have recently discovered that, in the vasculature lining neural tissues, VEGF only induced permeability when present on the tissue- but not the luminal side of the endothelial cells.  This strict sidedness was due to selective VEGF receptor 2 (VEGFR2) signalling on the abluminal (basal) side of the cells.  This project aims at establishing whether this intriguing sidedness of VEGF signalling is generally valid, e.g. also in the lung or dermis. The project also aims at dissecting and comparing the signalling network downstream of abluminal VEGFR2 and luminal VEGFR1.  This research will significantly enhance our understanding of the patho-physiological action of VEGF.

Key reference(s) (max. of 5):

  1. Betson, M., Martinelli, R., Ockrim, Z., Sarker, M.H., Fraser, P.A., Greenwood, J., Shima D. and Turowski, P. (….). Luminal VEGFR1 and abluminal VEGFR2 define VEGF signalling diversity in microvascular endothelial cells. (submitted) 
  2. Turowski, P., Martinelli, R., Crawford, R., Wateridge, D., Papageorgiou, A., Lampugnani, M.G., Gamp, A., Vestweber, D., Adamson, P., Dejana, E. and Greenwood, J. (2008). Phosphorylation of Vascular Endothelial Cadherin Controls Lymphocyte Emigration. J Cell Sci. 121, 29-37

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39. Making new blood vessels from embryonic stem cells

Supervisor(s):
Marcus Fruttiger

Department:
UCL Institute of Ophthalmology

Project outline (5-10 lines):
We aim to derive vascular cells and/or their precursors from embryonic stem cells in order to obtain a cell population that is suitable for cell therapy approaches in vaso-degenerative diseases such as diabetes. The project will investigate the factors that are involved in driving cell differentiation down the vascular lineage pathway. Students will also culture different cells types in combination to explore their potential to establish vascular structures in vitro. The project will be integrated in a collaborative effort within the UCL Institute of Ophthalmology (Dr. Fruttiger and Prof. P. Coffey), Industry and Moorfields Eye Hospital.

Key reference(s) (max. of 5):

  1. Benedito R, Roca C, Sörensen I, Adams S, Gossler A, Fruttiger M, Adams RH (2009)The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell 12; 137(6):1124-35.
  2. Chen FK, Uppal GS, MacLaren RE, Coffey PJ, Rubin GS, Tufail A, Aylward GW, Da Cruz L (2009) Long-term visual and microperimetry outcomes following autologous retinal pigment epithelium choroid graft for neovascular age-related macular degeneration. Clin Experiment Ophthalmol 37(3):275-85.
  3. Fruttiger M (2007) Development of the retinal vasculature. Angiogenesis 10(2):77-88
  4. West H, Richardson WD, Fruttiger M. (2005) Stabilization of the retinal vascular network by reciprocal feedback between blood vessels and astrocytes. Development 132(8):1855-62

[project40: 40] 40. Control of brain blood flow by neurotransmitters Supervisor(s): 
David Attwell

Department: 
Physiology (NPP)

Project outline (5-10 lines):  
Neural activity leads to increased blood flow in the brain, as a result of neuronally released glutamate generating messengers such as NO, adenosine, prostaglandins and other arachidonic acid derivatives which relax arteriole smooth muscle. We have shown that, in addition to this control of blood flow at the arteriole level, contractile cells called pericytes can also regulate brain blood flow. The project will involve studying how neurotransmitters regulate the contractile tone of these cells in brain slices.

Key reference(s) (max. of 5):

  1. Peppiatt, C.M., Howarth, C., Mobbs, P. & Attwell, D. (2006) Bidirectional control of CNS capillary diameter by pericytes. Nature 443, 700-704.
  2. Peppiatt, C. & Attwell, D. (2004) Food for thought. Nature 431, 137-138.

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41. Harnessing synergy between natriuretic peptides and phosphodiesterase 5 inhibitors for the treatment of heart failure

Supervisor(s):
Prof. Raymond MacAllister & Dr. Adrian Hobbs

Department:
Clinical Pharmacology (Medicine)

Project outline (5-10 lines):
Cardiac hypertrophy and heart failure are precipitated by a number of stress factors including hypertension and myocardial infarction. Recent pre-clinical and clinical studies have suggested that increasing cardiac cyclic GMP levels is likely to be of benefit in heart failure in terms of both symptomatic relief and anti-remodelling activity; this is particularly true of natriuretic peptides that stimulate cyclic GMP formation via activation of particulate guanylate cyclases and exert potent anti-hypertrophic effects. We have recently demonstrated that synergy between natriuretic peptides and phosphodiesterase type 5 (PDE 5; enzyme that inactivates cyclic GMP) inhibitors is beneficial in a model of pulmonary hypertension (i.e. right heart failure). In the current project we intend to investigate if this synergistic activity is also effective in preventing and/or reversing the development of left ventricular hypertrophy and heart failure. The programme of work will involve in vitro investigations in human cardiomyocytes, ex vivo studies in isolated (Langendorff) heart preparations and in vivo experimentation in models of heart failure. As such, the project will provide an excellent, broad-based training in in vitro and in vivo pharmacology.

Key reference(s) (max. of 5):

  1. Baliga, R.S., Zhao, L., Madhani, M., Lopez-Torondel, B., Visintin, C., Selwood, D., Wilkins, M.R., MacAllister, R.J. & Hobbs, A.J. (2008). Synergy between natriuretic peptides and phosphodiesterase 5 inhibitors ameliorates pulmonary arterial hypertension. Am. J. Respir. Crit. Care Med., 178, 861-9.
  2. Madhani, M., Okorie, M., Hobbs, A.J. & MacAllister, R.J. (2006). Reciprocal regulation of human soluble and particulate guanylate cyclases in vivo. Br. J. Pharmacol., 149, 797-801.
  3. Ahluwalia, A., Foster, P., Scotland, R.S., McLean, P.G., Mathur, A., Perretti, M., Moncada, S. & Hobbs, A.J. (2004). Anti-inflammatory activity of soluble guanylate cyclase: cGMP-dependent down-regulation of P-selectin expression and leukocyte recruitment. Proc. Natl. Acad. Sci. USA., 101, 1386-1391.
  4. Madhani, M., Scotland, R.S., MacAllister, R.J. & Hobbs, A.J. (2003). Vascular natriuretic peptide receptor-linked particulate guanylate cyclases are modulated by nitric oxide-cyclic GMP signalling. Br. J. Pharmacol., 139, 1289-1296.
  5. Hussain, M.B., MacAllister, R.J. & Hobbs, A.J. (2001). Reciprocal regulation of cGMP-mediated vasorelaxation by soluble and particulate guanylate cyclases. Am. J. Physiol., 280, H1151-H1159.

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42. The effect of acute exercise on psychobiological responses in participants with depressive symptoms

Supervisor(s):
Mark Hamer, Andrew Steptoe

Department:
Psychobiology Group, Department of Epidemiology and Public Health

Project outline (5-10 lines):
Mood disorders, including depression and anxiety, are risk factors for cardiovascular disease (CVD) (1). Variations in mood state across the day are associated with cardiovascular function and other health markers (2), which might play a role in CVD risk. Health behaviours such as exercise have immediate mood enhancing effects (3) and may also impact on psychobiological responses over the day. This effect, however, does not appear to be consistent across all participants. For example, some evidence suggests that depressed individuals have increased negative mood 30 min following exercise (4), which may partially explain reduced initiation and adherence to exercise programs in depression and exacerbate the risk of CVD (5). The mechanisms explaining the effects of exercise on mood remain poorly understood. The aim of this project is to examine the effect of a single bout of acute exercise on cardiovascular, biological, and mood responses throughout the day in participants with and without depressive symptoms.  This work will contribute to increasing the efficacy of exercise programs in depression, which is important for secondary and primary prevention of CVD.    

Key reference(s) (max. of 5):

  1. Van der Kooy K, van Hout H, Marwijk H, Marten H, Stehouwer C, Beekman A. (2007). Depression and the risk for cardiovascular diseases: systematic review and meta analysis. Int J Geriatr Psychiatry. 22, 613-26.
  2. Steptoe A, Wardle J, Marmot M. (2005). Positive affect and health-related neuroendocrine, cardiovascular, and inflammatory processes. Proc. Natl. Acad. Sci. USA 102, 6508–6512.
  3. Biddle SJH. (2000). Emotion, mood and physical activity. In, Biddle, Fox, Boutcher, Eds. Physical Activity and Psychological Well-being. Routledge, UK. pp.63-88.
  4. Weinstein AA, Deuster PA, Francis JL, Beadling C, Kop WJ (2009). The role of depression in short-term mood and fatigue responses to acute exercise. Int J Behav Med. Mar 31. [Epub ahead of print]
  5. Whooley MA, de Jonge P, Vittinghoff E, Otte C, Moos R, Carney RM, Ali S, Dowray S, Na B, Feldman MD, Schiller NB, Browner WS (2008). Depressive symptoms, health behaviors, and risk of cardiovascular events in patients with coronary heart disease. JAMA. 300, 2379-88.

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43. Development of percutaneous heart valve with nanocomposite polymer, peptides and stem cells

Supervisor(s):
Professor Alexander Seifalian & Dr Gaetano Burriesci

Department:
Division of Surgery & Interventional Science & Dept of Mechanical Engineering

Project outline (5-10 lines):
The project is an exciting one at the very fore-front of valve technology at present. If successful there could be a significant impact on patient care reducing inpatients stay and allowing wider access to treatment for some patient groups (those too sick for open surgery).

Development based on nanomaterial, tissue engineering and peptides, currently two postdoctorals and 1 PhD student working on it.

Key reference(s) (max. of 5):

  1. Ghanbari H, Viatge H, Kidane AG, Burriesci G, Tavakoli M, Seifalian AM. Polymeric heart valves: new materials, emerging hopes. Trends Biotechnol 2009;27:359-367
  2. Kidane AG, Burriesci G, Edirisinghe M, Ghanbari H, Bonhoeffer P, Seifalian AM. A novel nanocomposite polymer for development of synthetic heart valve leaflets. Acta Biomater 2009;
  3. de MA, Jell G, Stevens MM, Seifalian AM. Biofunctionalization of biomaterials for accelerated in situ endothelialization: a review. Biomacromolecules 2008;9:2969-2979
  4. Ghanbari H, Kidane AG, Burriesci G, Bonhoeffer P, Seifalian AM. Percutaneous heart valve replacement: an update. Trends Cardiovasc Med 2008;18:117-125
  5. Punshon G, Sales KM, Vara DS, Hamilton G, Seifalian AM. Assessment of the potential of progenitor stem cells extracted from human peripheral blood for seeding a novel vascular graft material. Cell Prolif 2008;41:321-335
  6. Rashid ST, Fuller B, Hamilton G, Seifalian AM. Tissue engineering of a hybrid bypass graft for coronary and lower limb bypass surgery. FASEB J 2008;22:2084-2089

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