Therapeutic approaches for codon reiteration diseases (360G-Wellcome-064354_Z_01_B)
I aim to develop therapeutic strategies for diseases associated with protein misfolding and intracellular aggregation, focussing on Huntington's disease (HD) and oculopharyngeal muscular dystrophy (OPMD). First, I will develop our findings that levels of mutant huntingtin fragments can be reduced by inducing autophagy. This strategy attenuates toxicity of the HD mutation in transgenic cell, fly and mouse models. Recent work in cell and fly models suggests that autophagy induction is beneficial for a much broader range of targets, including polyglutamine expansions underlying many spinocerebellar ataxias, and tau. Currently, the only autophagy-inducing drug that is known to reduce mutant huntingtin levels effectively in mammalian brains is rapamycin. While it is designed for long-term use, it has significant side-effects. My aims in the context of this component of the proposal are:1. Further the understanding of the machinery and regulation of mammalian autophagy to aid discovery of safer and more specific targets.2. Test autophagy upregulation as a therapeutic strategy for SCA3 and tauopathies in mouse models. Second, I will exploit our OPMD mouse model for testing 4 known safe drugs/compounds in vivo, on the basis of pilot data showing that they reduce aggregation and toxicity in OPMD cell models.
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Grant Details
Amount Awarded | 1645643 |
Applicant Surname | Rubinsztein |
Approval Committee | Clinical Interview Committee |
Award Date | 2006-06-05T00:00:00+00:00 |
Financial Year | 2005/06 |
Grant Programme: Title | Senior Research Fellowship Clinical Renewal |
Internal ID | 064354/Z/01/B |
Lead Applicant | Prof David Rubinsztein |
Partnership Value | 1645643 |
Planned Dates: End Date | 2012-08-31T00:00:00+00:00 |
Planned Dates: Start Date | 2007-01-01T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | East of England |
Sponsor(s) | Prof J. Paul Luzio |