Circuit Modulation in Spinocerebellar Ataxias: Mechanisms and Impact - Project Summary This proposal outlines a five-year career development plan aimed at guiding the principal investigator to independence as a clinician-neuroscientist with a focus on translational mechanisms and development of novel therapeutics for Spinocerebellar ataxias (SCAs). Applicant: Dr. Srinivasan has completed M.D. and Ph.D. degrees, residency training in neurology, and fellowship training in ataxia and movement disorders. He has extensive experience in biochemistry and cellular models, with specialized training in high throughput screening (HTS) and small molecule development. Over the past year, he has expanded his skillset to include animal models of disease and electrophysiology. His career development plan is designed to apply this skillset to the study of degenerative ataxias. The outlined plan includes mechanisms to enhance his training in genetic manipulation of neurodegenerative animal models, cerebellar electrophysiology, transcriptomics and bioinformatics. He will benefit from continued mentorship via regular meetings and collaborations. Additional research techniques will be acquired through formal coursework, workshops, and national meetings. Together, the training plan will provide Dr. Srinivasan with the skillset necessary for a successful independent research career in translational neuroscience. Research Plan: The SCAs are hereditary neurodegenerative disorders marked by progressive decline in appendicular coordination, speech, and gait instability, ultimately resulting in premature death due to cerebellar and brainstem dysfunction. Prior research has demonstrated that motor phenotypes in several of the most common SCAs are driven by aberrant firing of Purkinje neurons (PCs), which eventually degenerate. Currently, there are no approved therapeutics for any SCA, and a mainstay of clinical care is advocating for robust cardiovascular exercise. While exercise is helpful, the precise mechanisms driving the benefits of exercise remain largely undefined. Dr. Srinivasan's preliminary data demonstrates that exercise improves PC firing and rescues motor behavior. Combined with his published work that identified a tool compound that restores proper electrophysiological activity in SCA1 mouse models, Dr. Srinivasan is now positioned to probe whether exercise benefits derive from correcting PC firing (Aim 1) or additional pathways. He is also primed to mechanistically link PC firing to dendritic plasticity and eventual neurodegeneration (Aim 2), an important question in understanding the clinical ramifications of circuit correction as a therapeutic intervention. Collectively, the proposed studies will launch Dr. Srinivasan's career as an expert in disease pathogenesis in SCAs and position him to help discover and develop effective therapeutics for these fatal disorders.
