Dementia is the biggest health challenge of our century. To date, there is no way to prevent it or even slow its progression, and there is an urgent need to fill the knowledge gap in our basic understanding of the diseases that cause it.
The UK Dementia Research Institute (UK DRI) is the biggest UK initiative driving forward research to fill this gap.
Applications are invited for a Research Fellow to work on a Cure Huntington's Disease Initiative (CHDI) Foundation funded project within Professor Sarah J Tabrizi’s research group at the Huntington’s Disease Centre.
Recent genome-wide association (GWA) data has shown that the DNA damage response (DDR) pathway acts through somatic expansion of the CAG repeat to determine the age at onset (AAO) and rate of progression of Huntington’s disease (HD). This post will assist with the day-to-day running of a project that focuses on studying the role of DDR proteins in CAG repeat instability. The appointee will culture patient iPSC lines with at least 125 CAG repeats, and differentiate into disease-relevant cell types, including medium spiny neurons (MSNs). Cutting-edge techniques including CRISPR/Cas9 genome editing and knockdown through antisense oligonucleotide (ASO) and shRNA will be employed to manipulate expression of key components of the DDR pathway in iPSC-derived neuronal cells. The effect on SI will be monitored using CAG repeat sizing, and the appearance or alteration to HD phenotypes assessed using High Content Imaging (Opera Phenix). Effects on DNA repair and damage will be investigated in several ways including DNA repair reporter assays.
The post holder will be responsible for knockdown and overexpression of DNA repair proteins in patient iPSC-derived cells to assess their role in CAG repeat expansion. They will modulate transcription through the HTT CAG repeat in U20S cells to assess its role in repeat instability. These projects will involve the daily maintenance of human iPSC lines and differentiation to neuronal cultures. DNA damage and repair activity will be assessed and analysed with assays including γH2AX, 53BP1 and Comet and microsatellite instability.
Applicants must have an Honours degree and a PhD or other post-graduate qualification in a relevant biological discipline or related subject area. Extensive experience of working in experimental laboratory research, and tissue culture and molecular biology experience, including PCR assays and transduction/transfection of cells, is essential. Excellent oral and written communication skills, and good inter-personal skills with an ability to work co-operatively in a multidisciplinary setting are also required. Experience of DNA repair or cancer DNA biology, iPSC cultures and biochemical assays including western blotting, and an understanding of neuroscience and neurodegenerative diseases, are desirable.
For informal enquiries concerning the post, please contact Dr Michael Flower michael.flower@ucl.ac.uk
Appointment at Grade 7 is dependent upon having been awarded a PhD; if this is not the case, initial appointment will be at Research Assistant Grade 6B (salary £31,542 - £33,257 per annum) with payment at Grade 7 being backdated to the date of final submission of the PhD thesis.
