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High-probability grants
According to our matching algorithm, Kara L. Gordon is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2011 |
Gordon, Kara |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Investigating Mechanisms in Torsiona Proteasomal Degradation
DESCRIPTION (provided by applicant): DYT1 dystonia is an early onset inherited neurological disorder characterized by involuntary twisting movements. It is an autosomal dominant disorder with a penetrance of only 30-40% among mutation carriers. Factors behind the reduced penetrance in DYT1 dystonia are critical but poorly understood. DYT1 dystonia is caused by a mutation in the gene TOR1A that corresponds to the deletion of a glutamic acid residue (?E) in the C-terminal end of the protein torsinA. TorsinA is an endoplasmic reticulum (ER) resident AAA+ ATPase. Important structural features of torsinA are its N-terminal hydrophobic domain that peripherally associates with the ER membrane and two asparagine residues that are modified by addition of N-linked high mannose glycans. TorsinA(wt) has been shown to be degraded by macroautophagy while torsinA(?E) is a target for rapid degradation by the ubiquitin proteasome pathway (UPP), suggesting that cells may utilize degradation as way to favorably modify the ratio of torsinA(wt) to torsinA(?E) in neurons and perhaps modify the pathogenesis of DYT1 dystonia. Proteins can be recognized by chaperones as substrates for degradation by the proteasome due to exposed hydrophobic patches or available N-linked glycan groups. The (?E) mutation may be responsible for revealing one of these motifs to the protein quality control machinery inside the ER. This research plan will test the hypothesis that the N-terminal hydrophobic domain is the motif on torsinA(?E) that targets it for degradation by the UPP and that the high-mannose glycans on torsinA(?E) are recognized by a candidate E3 ubiquitin ligase for ubiquitination. Aim 1 will investigate the motif that targets torsinA(?E) to the proteasome. Experiments investigating the half-life, degradation pathway, and subcellular location of torsinA(wt) and torsinA(?E) constructs lacking the N-terminal hydrophobic domain or the two glycosylation sites will be performed to determine the role of each motif on UPP targeting. Aim 2 will determine a ubiquitin ligase involved in the ubiquitination of torsinA(?E). Acceptor photobleaching FRET (fluorescence resonance energy transfer) will be used to determine if torsinA(?E) with and without glycosylation sites interacts with a candidate E3 ubiquitin ligase in vivo, and an immunoprecipitation-based approach will be used to determine if the ligase ubiquitinates torsinA(?E). The goal of this proposal is to understand mechanistic aspects behind two critical steps of the proteasomal degradation of torsinA(?E). PUBLIC HEALTH RELEVANCE: Efficient degradation of disease-linked proteins is critical in several neurological diseases and may be implicated in the development of DYT1 dystonia, an inherited disease where only 30%-40% of the mutation carriers manifest clinical symptoms. Prior research suggests that neurons use protein degradation as a way to favorably dispose of the DYT1-associated mutant protein. Investigation into the specific mechanisms of degradation will enhance our understanding of factors that influence DYT1 dystonia development and may reveal potential therapeutic targets modulating protein degradation.
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