Summary

I will elucidate how disrupted lysosomal activity in microglia contributes to the pathology in Alzheimer’s disease (AD) using large-scale CRISPR mutagenesis screens of genes associated with AD risk.As a postdoctoral researcher, I have identified a lysosomal transcriptional network necessary for the survival and function of microglia. I am currently building upon my observation to functionally define a lysosomal network in microglia that is disrupted in Alzheimer’s disease (AD). Despite the wealth of genomic data available from AD patients, the functions of most genes associated with AD risk loci remain uncharacterized. As an independent researcher, I will elucidate the functions of AD risk-associated genes in microglia, with a special focus on genes functioning in lysosomal pathways.

Project Details

Despite strong evidence indicating that microglial dysfunction is a core feature of Alzheimer’s disease (AD), it remains unclear how genes associated with AD risk loci affect microglial function, and how disrupted microglial function, in turn, can impact the onset or progression of AD. The large-scale, screen-based approach I propose is necessary to provide the first insight into the functions of most genes associated with AD risk loci and will bridge the gap between the rich genomic resources available for AD and the molecular mechanisms underlying this devastating disease. My study will lead to a deeper understanding of lysosomal gene networks necessary for microglial function, which can be harnessed to develop effective therapeutic strategies for Alzheimer’s disease (AD) by modulating lysosomal activity. Furthermore, I anticipate that my proposed large-scale functional genomics screen of genes associated with AD risk loci will: a) illuminate novel functions for genes mutated in AD, and b) reveal novel genes associated with the pathology of AD. Collectively, my proposed research will have a tremendous positive impact on AD, microglia, and zebrafish communities.