Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY The goals of this R01 Supplemental award are to: 1) find common and distinct themes of degeneration and neuroprotection in the family of polyglutamine (polyQ) disorders; and 2) enhance the professional and scientific training of Dr. Oluwademilae Nuga, postdoctoral fellow in the Todi laboratory at Wayne State University School of Medicine. The polyQ family comprises nine incurable diseases: Spinocerebellar Ataxias (SCAs) 1, 2, 3, 6, 7 and 17, Huntington's disease (arguably the most famous member of the family), Dentatorubral-pallidoluysian atrophy and Spinal and Bulbar Muscular Atrophy (also known as Kennedy's Disease). Much has been learned about the biology of disease in the polyQ family, yet we lack therapeutic interventions in the clinic, indicating that we still have much to learn about mechanisms underscoring them. Here, we propose to conduct unbiased and hy- pothesis-targeted studies in mammalian cells and in Drosophila models of disease to uncover common themes of disturbance at the cellular and animal level. The work that we propose seeks to enhance ongoing research in the Todi lab, funded under R01NS086778 (2014-2028). Specifically, the studies outlined for the two year timeframe of this proposal will use RNA-Seq and unbiased proteomics from cells stably expressing full-length, wild type and disease-causing polyQ proteins to undertake an unprecedented “birds-eye view” of shared and distinct mechanisms of degeneration. Unbiased studies will then be conceptualized into targeted hypotheses to confirm and extend them in animal models of disease and in patient-derived iNeuronal cells. The Todi lab recently completed the generation of a unique, unprecedented family of isogenic Drosophila lines that express the wild-type or pathogenic version of each polyQ protein that Dr. Nuga will use in this proposal. Alongside the scientific work, Dr. Nuga will undergo thorough mentoring for further scientific and professional growth, ensuring that by the end of this proposal she is very well positioned to apply for a K99/R00 award fo- cused on her own data, which she can then build towards an independent career in academia.
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