Harini Iyer, PhD
My long-term research goal is to identify and characterize genes functioning in the neuroimmune system in Alzheimer’s disease (AD). During my postdoctoral training, I have uncovered a lysosomal regulatory circuit that is essential for the early development of microglia in zebrafish. My data show that repression of the key lysosomal transcription factors, TFEB and TFE3, is essential for the normal development and function of microglia. In the next phase of my postdoctoral training, I will extend this observation to identify targets of TFEB and TFE3 in microglia that are disrupted in AD. As an independent researcher, I will leverage my postdoctoral training in microglia biology and lysosomal function to systematically probe the functions of genes associated with AD risk. Genome-wide association studies show that immune-related and microglial genes are significantly enriched in AD risk loci; however, the functions of most genes associated with AD risk loci remain uncharacterized. I will capitalize on the experimental tractability of zebrafish for performing large-scale CRISPR mutagenesis screens and in vivo imaging of microglia to create a functional framework for understanding the role of microglial and lysosomal dysfunction in AD. My proposed research will reveal a lysosomal gene network that is dysregulated in AD and will have important implications for targeted therapeutic strategies that modulate lysosomal activity in AD.