BioE PhD Proposal Presentation- Sara Bitarafan

Advisor:  Levi B. Wood, Ph.D. (Woodruff School of Mechanical Engineering, Georgia Institute of Technology)

Thesis Committee:

Young Jang, Ph.D.  (Emory Musculoskeletal Institute, Department of Orthopedics, Wallace H. Coulter Department of Biomedical Engineering, Emory School of Medicine & Georgia Institute of Technology)

Melissa Kemp, Ph.D. (Wallace H. Coulter Department of Biomedical Engineering, Emory School of Medicine & Georgia Institute of Technology)

Srikant Rangaraju, M.D. (Department of Neurology, Yale University)

Annabelle Singer, Ph.D. (Wallace H. Coulter Department of Biomedical Engineering, Emory School of Medicine & Georgia Institute of Technology)

Re-wiring CSF1-R Signaling in Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common cause of dementia, affecting over 6.9 million people in the US, a number projected to double by 2060 without a cure. Emerging evidence highlights the role of the brain’s immune system, particularly microglia, in AD-related neurodegeneration and cognitive decline. Microglia, the brain’s immune sentinels, transition from a protective "homeostatic" state to a "disease-associated" state (DAM) under chronic AD pathology, impairing phagocytosis, disrupting immune activity, and accelerating neurodegeneration. Microglial immunological shift and phenotypic transformation are orchestrated by variety of signaling pathways and cell surface receptors like colony-stimulating factor-1 receptor (CSF1-R). CSF1-R, expressed primarily on microglia in the brain, governs key processes including phagocytosis, polarization, and proliferation. Studies suggest that CSF1-R-mediated microglial depletion can improve cognitive function in AD models. However, the mechanisms by which Aβ accumulation alters CSF1-R signaling to disrupt microglial function and drive disease progression remain unclear, necessitating further investigation. My hypothesis is that CSF1-R control of downstream signaling events and microglial phenotype are perturbed by exposure to Alzheimer’s disease pathogen Aβ. The goal of this research proposal is three-fold: (Aim 1) determine how Aβ interacts with CSF1-R and its effect on specific CSF1-R phospho-site activity and its downstream signaling cascades in vitro, (Aim 2) illuminate how dysregulated CSF1-R-mediated signaling impacts microglial phenotypes and neuroimmune activity in vitro and in vivo  and (Aim 3) identify AD-driven proteomic and transcriptomic signatures associated with CSF1-R activity and downstream signaling from human samples. This research proposal aims to provide a mechanistic insight into how AD pathology alters CSF1-R signaling and its downstream effectors. Identifying mechanisms through which disturbed CSF1-R signaling contributes to DAM phenotype, disturbed neuroimmune activity and pathogenesis in AD could ultimately lead to a new paradigm for AD therapeutic development.