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UCL Great Ormond Street Institute of Child Health

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Dr Dagan Jenkins

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Telephone number: 0207 905 2838

Publications


Background

The main focus of our lab is to investigate the pathogenesis and treatment of skeletal ciliopathies.

Cilia are microtubular protrusions present on the surface of most cells. Mutations that disrupt the function of cilia have been identified in many human diseases, and abnormal ciliogenesis is associated with a characteristic set of human phenotypes, the 'ciliopathies'. At least 90 causative genes have been identified in ciliopathies, and collectively it is estimated that approximately 1 in 1000 people may be affected by this category of disease. These include a number of important human diseases such as renal cystic disease, obesity and retinal degeneration. Therefore, investigating the mechanisms of pathogenesis in relation to cilia has potentially broad implications for the treatment of a variety of important diseases.

A subset of ciliopathies, including Jeune, Carpenter and Sensenbrenner syndromes, feature particular skeletal involvement in addition to some of the classical ciliopathic phenotypes. These include abnormal development of the skull (craniosynostosis), rib cage and long bones. Unlike classical ciliopathies, these so-called 'skeletal ciliopathies' are typically caused by mutations in genes encoding ciliary trafficking proteins, including core components of intraflagellar transport (IFT) and vesicle transport machinery.

One of the main interests of our lab is therefore to investigate the mechanisms that regulate ciliary trafficking. Another active area of research focuses on neural crest cells (NCCs). There is growing evidence that skeletal defects, such as craniosynososis, cardiac malformations and neurological abnormalities/learning defects found in ciliopathies may be caused by abnormal specification, differentiation and/or migration of NCCs. We are therefore also actively exploring the mechanisms that regulate NCC development, and possible therapeutic manipulation of these cells.


Main Interests/Achievements

Investigating ciliary trafficking in the pathogenesis and treatment of ciliopathies

All types of cilia lack the necessary machinery for protein synthesis. Therefore, all proteins required for ciliary function must first be transported to the membrane and/or base of cilia in specific vesicles. As such, defects in ciliary trafficking lie at the heart of all ciliopathies. Our lab therefore focuses on the skeletal ciliopathies with a view to understanding the mechanisms that regulate ciliary trafficking and developing therapeutic approaches that may be more widely relevant to all ciliopathies.

Two complimentary approaches are used:

 1. Tandem-affinity purification (TAP) and SILAC are used to identify and characterise novel ciliary trafficking proteins, and gene knockdown/mutation in cell lines and model organisms is used to test the potential of manipulating ciliary trafficking for therapy.
 2. High-throughput microscopy-based small molecule screens are undertaken to identify compounds that target ciliary trafficking, and drug hits are tested for their therapeutic potential in cell lines and model organisms.

Targeting neural crest cell fates for the treatment of birth defects and tumours

Neural crest cells (NCCs) are multipotent cells that follow highly specific migratory paths to populate a number of tissues in developing embryos. They subsequently differentiate into a variety of cell types, including cartilage, neurons, cardiomyocytes and melanocytes. Growing evidence has suggested that cilia are present on the surface of NCCs and their derivatives, and that abnormal specification, differentiation and/or migration of NCCs contributes to skeletal and cardiac defects, as well as Hirschsprung's disease, in ciliopathies. The hypothesis that we are currently testing is that factors that influence NCC identity or migration may be used for treatment of ciliopathies and other NCC-derived defects (including specific tumours).


Three specific approaches are used:

 1.
Chemical and genetic screening is undertaken to identify novel genes and FDA-approved drugs that influence NCC development in zebrafish embryos.
 2.
These factors are tested for their ability to treat skeletal ciliopathies (e.g craniosynostosis) in model organisms and to inhibit growth of NCC-derived tumour cell lines.
 3. Genes encoding key ciliary trafficking proteins are mutated specifically within NCCs in mice (using a Cre-lox approach), and resulting skeletal defects and other neurocristopathies are characterised.

Grants

Research Funding

11/13 - 10/16
MRC New Investigator Research Grant: Nudc as a new molecular target to investigate the pathogenesis and treatment of skeletol ciliopathies
05/12 - 10/12
UCL SLMS "Investing in Excellent Researchers" Award
02/11 - 05/11
Wellcome Trust ViP Award
04/07 - 03/10
MRC Project Grant: RAB23 mutations and insight into craniosynostosis