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Structure-guided development of biologics and small molecule approaches to manage genetic diseases

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

Project Description

A stipend-supported graduate student position at the M.Sc. or Ph.D. level is available to carry out structural biology research to advance therapeutic strategies to treat genetic diseases. We seek an energetic individual with a strong background in biochemistry and molecular biology.

The successful candidate will embark on exciting project that focuses on developing biologic and structure-based (protein X-ray crystallography) development of small molecule approaches to manage protein/enzyme deficiencies arising from heritable genetic mutations. In particular, we are interested in Tay-Sachs disease and Sandhoff Disease (also knows as the GM2 gangliosidoses), which are are inherited neurodegenerative diseases that result from genetic mutations that inactivate an enzyme known as HexA. HexA is a lysosomal enzyme that degrades GM2-ganglioside (GM2), a molecule found primarily on neurons of the central and peripheral nervous system. Loss of HexA activity results in rapid accumulation of GM2 in neurons and severe neurological deterioration.

Importantly, HexA activity as low as 10% can prevent, and possibly reverse, GM2 accumulation and the associated neurodegeneration. We hypothesize that a therapy for infantile and late-onset forms of GM2 gangliosidosis is achievable by supplementing patients with active Hex enzyme (i.e. enzyme replacement therapy), and in late-onset cases, combing enzyme replacement with drugs known to boost residual Hex activity to bring the total Hex activity above the critical 10% activity threshold. We have recently engineered HexA based on X-ray structures to markedly improve its stability and function for enzyme replacement therapy. We now propose to use the engineered enzyme, known as HexM, to develop an enzyme replacement therapy that will be evaluated in mouse models of GM2 gangliosidosis in combination with a drug known to rescue residual HexA activity in cells. The approach holds promise to reduce GM2 accumulation and reverse the progression of this debilitating family of neurological diseases.

More recently, we are also embarking on an X-ray structure-based approach to develop new small molecule-based strategies to bolster the activity of mutated forms of glucocerebrosidase. Heritable loss-of-function mutations in glucocerebrosidase give rise to another serious genetic disease known as Gaucher’s disease. Mutations in glucocerebrosidase are also associated with Parkinson’s disease. This project will involve X-ray crystallographic studies of glucocerebrosidase bound to small molecules aimed as rescuing the activity of mutant forms of the enzyme to alleviate symptoms of the disease. These molecules are known as pharmacological chaperones and are synthesized in collaboration with our chemical biologist colleagues.

The research projects available on these genetic diseases offer rich training opportunities in molecular biology, protein chemistry, structural biology and cell biology. The interdisciplinary nature of the research will provide the skills that can be applied to a scientific career in academia, industry or government.

Additional information about our research and recent publications in the area can be found at: http://home.cc.umanitoba.ca/~bmark
Candidates must hold a B.Sc. in biochemistry or related field. Training in mammalian cell culture and protein purification would be considered an asset. Biochemistry, molecular biology and structural biology research will be at the core of the projects.
We are located in the Department of Microbiology, University of Manitoba, Winnipeg, Canada. The laboratory offers state-of-the-art biochemistry and molecular biology research tools, as well as a protein X-ray crystallography facility for complete gene to structure and function research.

The University of Manitoba (http://umanitoba.ca/) is the largest University in the province (over 30,000 students, faculty, and staff) and hosts a dynamic agricultural and biomedical research community. Winnipeg is a vibrant, multicultural city with numerous cultural events and festivals (http://www.destinationwinnipeg.ca/).

All qualified candidates are encouraged to apply.

Please direct formal and informal inquiries and CV’s (including names of three referees) to Dr. Brian Mark.
NOTE: Given the large volume of applications, you may only receive a reply back if you are shortlisted for an interview.

Funding Notes

This graduate student position is supported by a research grant (Canadian Institutes of Health Research) held by the supervisor.

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