Wellcome Trust PhD Student Cohort 2017
Academic and Work Experience Prior to Sept 2017 Programme Start: I completed a BSc in Biological Sciences at Imperial College London, with a year in Industry where I worked in R&D at GlaxoSmithKline in Stevenage.
PhD Programme – Year 1 – MRes and Project Rotations: In my first year, I wanted to explore many different areas and techniques in stem cell biology. During my first rotation with Dr Tamir Rashid, I investigated the role of the IFNy/STAT1 axis on the culture of iPSC-derived hepatic progenitor cells with a view to explore this novel cell population, and improve iPSC-derived hepatocyte transplants in liver disease. In my second rotation with Professor Eric So, I aimed to determine molecular and phenotypic differences in leukemic stem cells derived from two different cells of origin; haematopoetic stem cells versus chronic myeloid progenitors. In my final rotation with Dr Ivo Lieberam, I learned how to differentiate wildtype and mutant iPSCs into cortical neurons in order to examine Alzheimer’s-associated phenotypes in a cellular model of disease. Overall, these three rotations improved my experience with cell culture, functional assays, molecular biology, cloning and imaging, and confirmed my desire to work in neuroscience.
PhD Programme – Years 2 to 4 – Doctoral Studies: For my PhD project I have joined Professor Chris Shaw’s Lab and will be working closely with Dr Ivo Lieberam as my second supervisor. My project will focus amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease characterised by loss of motor neurons and muscle wasting. ALS can be driven by a plethora of distinct genetic mutations. I will be investigating one such novel mutation in iPSC-derived motor neurons. We predict that the respective mutant protein may respond to excitotoxicity (a widespread phenomenon in ALS), and contribute to the pathological protein aggregation that is a hallmark of approximately 97% of cases of ALS. In my project I will use optogenetics to accurately photostimulate wildtype and mutant iPSC-derived motor neurons, thereby recapitulating excitotoxicity. Any phenotypic responses to this stimulation will be assessed by live imaging. First, we aim to determine if our target mutant protein accumulates in response to excitotoxicity. Second, we aim to assess whether these aggregates are dysregulated and pathogenic. Finally, we aim to not only determine the cellular response in motor neurons alone, but also to explore how any changes affect neuromuscular junctions using a novel compartmentalised microfluidic device developed by the Lieberam group. In conclusion, this work should improve the in vitro modelling of ALS, and uncover novel pathological mechanisms of action of our target mutant protein for the first time.
Gaby Clarke ORCID webpage