Understanding the Microglia Cell-Surface in Alzheimer’s Disease
MentorJames Wells, PhD The University of California
I will use a combination of proteomics, functional genomics, and protein engineering to understand how human microglia remodel their cell surface in Alzheimer’s Disease.
In Aim 1, I will explore the changes that microglia undergo when they encounter protein aggregates such as Aß42 and tau. To accomplish this, I will use mass spectrometry techniques that focus on the cell-surface of microglia. In Aim 2, I will use a genetic screening approach to find novel regulators of microglia Aß42 and tau phagocytosis. In Aim 3, I will test a panel of novel recombinant antibodies against microglia cell-surface targets for their ability to modulate microglia activity. Function-modulating antibodies may serve as a novel treatment paradigm for Alzheimer’s disease.
This proposal uses a combination of cutting-edge techniques including iPSC biology, cell-surface proteomics, functional genomics, and antibody engineering to tackle core questions of microglia biology in the context of Alzheimer’s disease. The aims are independent but interwoven to provide the most direct pathway to identifying and targeting disease-relevant proteins. The focus of my proposal is the identification of novel microglia disease targets and the immediate generation of recombinant antibodies to modulate these proteins. This pipeline directly couples discovery biology to therapeutic development using human iPSC-derived microglia.