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Inhibition of the translation of huntingtin as a therapeutic mechanism to treat Huntington’s disease:
Huntington’s disease (HD) is a rare neurodegenerative disorder caused by an expanded polyglutamine stretch in the huntingtin protein (HTT) that results in misfolding and aggregation of the mutant form of HTT (mHTT). Almost 20 years after the discovery of the causative gene for HD, a disease modifying treatment has yet to be developed. Translational stalling is a mechanism found in nature where a co-effector molecule (usually a small metabolite) binds to the ribosome as it translates and acts in concert with the nascent peptide to prevent further elongation or termination. The aim of this postdoctoral proposal is to demonstrate a proof of concept that decreasing mHTT protein levels via translational stalling is a viable therapeutic strategy for the treatment of HD.
1. To genetically engineer a translational stall in the uORF of the mHTT locus via introduction of a eukaryotic stalling sequence such as arginine attenuator peptide in HD patient derived induced pluripotent stem cells (HD-iPSC).
2. To characterize the impact of mHTT translational stalling on disease relevant endpoints or cellular phenotypes in these engineered HD-iPSCs
3. To examine the natural regulation of the htt gene in specific cell types in the mouse brain and in patient derived HD-iPSCs.
*PhD in Neuroscience is required.
*Stem cell biology expertise is desired
*Strong molecular and cellular biology skills are required
*Demonstrated attention to detail and problem solving skills; effective time management and experiment planning skills
*Effective written and oral communication skills are necessary
We seek a highly motivated individual with a demonstrated track record in basic or translational neuroscience and stem cell biology for this postdoctoral fellowship. The candidate’s studies will focus on generating engineered iPSC, differentiating HD iPSC to MSN and functional characterization of these cells. Additionally ribosomal profiling will be conducted to understand the natural regulation of the htt gene in both normal and HD-patient derived iPSCs.