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

Committee Members:

Hang Lu, Ph.D. (School of Chemical and Biomolecular Engineering, Georgia Institute of Technology)

Edward Botchwey, Ph.D. (Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University)

Zhexing Wen, Ph.D. (Department of Psychiatry and Behavioral Sciences, Emory School of Medicine)

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

Harnessing MAPK/ERK Signaling with Receptor Tyrosine Kinases to Control Alzheimer's Disease Associated Microglia

In the Alzheimer’s disease brain, a subset of the brain resident immune cells, microglia, transition from a homeostatic population to an activated disease associated microglial (DAM) phenotype. These microglia possess hyperactivation of the ERK signaling protein and some protective functions. Preliminary analysis utilizing a computational model of cell signaling networks identified two receptor tyrosine kinases, CSF1R and TGFBR1/2, that are upstream of the MAPK/ERK pathway and have the capacity to modulate the DAM phenotype in vitro and in vivo and alter therapeutically relevant microglial function. Interestingly, despite the convergent signaling through the MAPK/ERK pathway by these receptors, there is a divergent functional response. CSF1R acts as a pro-DAM receptor, and TGFBR1/2 acts as a checkpoint on the transition into DAM. This work seeks to provide a clear mechanism of how these receptors signal through the MAPK/ERK pathway, including the specific temporal dynamics of activation, and determine the therapeutic relevance of targeting these receptors. Specifically, Aim 1 will validate the role of these receptors and their interaction with the MAPK/ERK pathway using proximity labeling of proteins. Aim 2 will deploy a real-time reporter system of ERK phosphorylation to establish the dynamics of ERK activation associated with the DAM phenotype. Aim 3 will target these receptors with inhibitors in a mouse model of Alzheimer’s disease and assess therapeutic potential. Together, this work will fill critical gaps in Alzheimer’s pathophysiology and identify novel therapeutic avenues to target microglia.