The dual goals of my proposal are to define the contribution of fatty acid elongases and long chain fatty acids to ?-synuclein neurotoxicity and to provide me with outstanding training and career development opportunities. I will use an innovative approach that combines the precision of Drosophila genetics with state-of-the-art patient derived IPSC neurons. First, I will identify novel lipid modifiers of ?-synuclein neurotoxicity using a powerful new Drosophila model of Parkinson?s disease and related ?-synucleinopathies. I will define the mechanism of action of these lipid modifiers in in vivo and in patient-derived neurons. My ultimate goal in the proposed studies is to identify novel lipid therapeutic targets for ?-synucleinopathies, including Parkinson?s disease. By completing this proposal, I will gain critical scientific training in diverse model systems, which will enrich my existing skillset. The career development plan has been carefully crafted to support my goal of becoming an independent investigator in neurodegenerative research. My mentor, Dr. Mel Feany, is an internationally recognized expert in neurodegeneration and a pioneer in Drosophila modelling of neurodegenerative diseases, including Parkinson?s disease. The institutional resources available through Harvard Medical School affiliations and Brigham and Women?s Hospital, will support my growing research ambitions in an environment that can foster meaningful contributions and collaborative endeavors. At the end of my F32 fellowship, I will be ideally positioned to apply for the K99/R00 pathway to independence transition award or similar career award, through which I will continue to address fundamental questions in lipid metabolism related to neurodegenerative disease using an integrated, multifaceted experimental approach.
Using the powerful tools of Drosophila genetics and patient-derived neurons, my proposal seeks to identify lipid modulators of neurodegeneration in Parkinson?s disease and related disorders, termed ?-synucleinopathies. The overall approach of my studies is to discover novel modifiers and mechanisms in an established Drosophila ?- synucleinopathy disease model, validate the importance of the modifiers identified in mammalian systems, and use a multifaceted approach to define the mechanism of action of proteins and pathways discovered. The long- term goal of this research is to generate novel and targetable lipid-based therapeutic options for Parkinson?s disease and related disorders, which are incurable and devastating diseases.