Close
Supervisors names
Gabriel Galea
Kenzo Ivanovitch
JP Martinez-Barbera
Background
The Galea lab studies severe malformations of the brain and spinal cord called neural tube defects, which include spina bifida. We use a combination of animal, computational and iPSC models aiming to improve prevention and patient outcomes for these conditions. The group has internationally-recognised expertise in advanced microscopy (e.g. Galea et al Nat Commun 2021), embryo live imaging (e.g. Maniou et al PNAS 2021) and dissecting the biomechanical basis of neural tube development (e.g. Ampartzidis et al Dev Biol 2023).
Genetic mutations, environmental agents and gene/environment interactions all contribute to the causation of neural tube defects. Treating pregnant mice with molecules which cause DNA damage in their embryos, at concentrations which do not cause the embryos to die, is well-established to cause neural tube defects. While there is a tremendous body of literature on how DNA damage can cause cancer, far less is known about how it causes structural birth defects. DNA-damaging agents which have this effect include some pollutants1, alcohol2, and radiation3. We hypothesise that DNA damage initiates maladaptive cellular stress responses which enable the cell to survive but impair normal morphogenesis. One such maladaptive response could be the induction of cell senescence, which may disrupt the function of the affected cells as well as unaffected cells around them (“non-autonomous” effect).
Aims
To test this hypothesis we propose to:
1. Examine the temporal relationship between the onset of DNA damage stress, its resolution, and impairment of neural tube closure in cultured mouse and chick embryos.
2. Compare relevant cellular behaviours, such as accumulation of senescent nuclei, between healthy embryos and those with DNA damage.
3. Establish whether DNA damaging and senescence-inducing agents interact with genetic predisposition to spina bifida to increase risk of developing this condition.
Methods
This PhD will use mouse whole embryo culture, advanced microscopy, computational image analysis, molecular biology techniques such as PCR and use of transgenic mice for disease modelling. The student would also be involved in the lab’s public engagement activities and would have opportunities to be involved in teaching.
Timeline:
The student would learn to perform mouse whole embryo culture and microscopy techniques in the first three months. They would address Objective 1 in months 4-12, Objective 2 in months 13-18, and Objective 3 in months 19-36, aiming to submit publications before the end of their PhD. They would attend major conferences in years 2 and 3.
References
1. Lin et al Free Radic Biol Med. 2018 Feb 20;116:149-158.
2. Langevin et al Nature. 2011 Jul 6;475(7354):53-8.
3. Inouye et al Environ Med. 1997 Oct;41(1):40-2.
Contact
Gabe Galea, g.galea@ucl.a.uk