Resolving ubiquitin-dependent degradation of misfolded proteins using advanced single-molecule techniques. (360G-Wellcome-101585_Z_13_Z)
My proposed research seeks to understand the links between degradation of protein aggregates and the ubiquitin-proteasome pathway. The project entails three goals. The first goal involves establishing a fluorescence-based system to detect individual interactions between aggregates and proteasomes. To achieve this, I will initially receive training on proteasome purification and examine how to modify proteins with specific ubiquitin chains. Subsequently, I will explore different fluorescence labe lling systems and optimise a labelling strategy for protein aggregates and the proteasome without disrupting their integrity. The fluorophores selected should be bright and photostable to be compatible with the single-molecule instruments. This single-molecule fluorescence system will be used to establish a method that can reveal interactions between individual protein aggregates and a single proteasome to determine the efficiency of degradation for different types of aggregates. The second goal will focus on aggregate degradation in cells using three-dimensional superresolution imaging. Heterogeneous interaction between aggregates and proteasomes can be resolved to determine whether certain types of aggregates can inhibit the proteasome. Finally, I will focus on cell lines with mutations on key Parkinson's disease-related genes, and establish whether aggregate degradation is affected. Identifying altered degradation in these cells will relate proteasome functions directly to disease s tates.
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Grant Details
Amount Awarded | 250000 |
Applicant Surname | Ye |
Approval Committee | Basic Science Interview Committee |
Award Date | 2013-06-05T00:00:00+00:00 |
Financial Year | 2012/13 |
Grant Programme: Title | Sir Henry Wellcome Postdoctoral Fellowship |
Internal ID | 101585/Z/13/Z |
Lead Applicant | Dr Yu Ye |
Partnership Value | 250000 |
Planned Dates: End Date | 2018-05-31T00:00:00+00:00 |
Planned Dates: Start Date | 2014-06-01T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | East of England |
Sponsor(s) | Prof David Klenerman |