The goal of the proposed study is to identify signaling pathways that regulate phagocytic activity of microglia as a potential therapeutic strategy to treat Alzheimer’s Disease (AD). While genetic data is pointing to failure in myeloid phagocytic machinery, histological data indicates a failure in microglial barrier formation around the plaques. My proposal addresses whether activation of microglial phagocytic signaling is necessary for microglial barrier formation around the plaques. Identifying druggable phagocytic signaling proteins that regulate microglial barrier function has the potential to provide alternative therapeutic tools in the treatment of AD. As a postdoctoral fellow in Dr. Anne Schaefer’s Laboratory, I unraveled region-specific regulation of microglia clearance activity in the adult brain, an epigenetic mechanism for this regulation, and its importance for the normal brain function. This study, published in Nature Neuroscience, not only provided answers to long-debated questions on the existence, regulatory mechanism, and biological significance of microglial diversity in brain regions, but it also provided a methodological advance in microglial profiling strategies by avoiding artificial activation of microglia that is commonly seen during their purification.
During my postdoctoral training, I have also participated in a number of collaborations around the world that revealed different aspects of microglial specialization during development and disease. Our most recent research focuses on elucidating the mechanisms of brain region-specific microglia-neuron interactions. This is an important question, since imbalances in neuronal activity are a common trait in most neuropsychiatric and neurodegenerative disorders and microglia are long thought to modulate neuronal activity, though exact mechanisms are unknown. In addition, as part of the Loeb Center for Alzheimer’s Disease, we unraveled a molecular and cellular mechanism by which lower levels of myeloid PU.1 transcription factor delay AD onset in humans. Since my graduate years, I have been committed to the development of novel, cutting edge technologies in the field of neuroscience that allow cell-type specific analysis. I believe that my strong background in microglial biology and molecular biology, as well as technical expertise in developing highly innovative in vivo molecular tools position me as a uniquely prepared candidate to tackle this challenge.