Autophagy in Microglial Activation and Neuroinflammation
Scientists now believe that chronic inflammation of the brain is an important cause of Alzheimer’s disease and treating inflammation can reduce one’s chance of getting the disease. From research studies, we know which types of brain cells are most important for causing the brain inflammation, but do not have a good understanding of why and how this occurs. The proposed study will help us answer these important questions. It may allow us to find new ways to treat brain inflammation to slow or prevent the disease.
The goal of my project is to understand the critical signaling pathways that underlie microglial inflammatory response in the context of Alzheimer’s disease (AD) pathogenesis. I am investigating the hypothesis that basal autophagic activity acts to negatively control microglial inflammatory response and that AD-associated toxic/risk signals inhibit autophagy to activate microglia.
First, in Specific Aim I, I am determining the role of p38 mitogen-activated protein kinases (MAPK)-dependent phosphorylation of ULK1 [Serine/threonine-protein kinase 1] in inflammatory stimulus-mediated inhibition of autophagy and microglial activation. This is accomplished by studying whether p38 MAPK directly regulates ULK1 kinase activity to affect autophagy in microglia, and whether inhibition of autophagy via p38 MAPK-ULK1 is required for microglial inflammatory response to stimulus. Second, in Specific Aim II, I am studying whether AD-associated toxic/risk signals act through the p38 MAPK-ULK1/autophagy pathway to modulate microglial activity in cultured cells. This is accomplished by determining if abeta and triggering receptor expressed on myeloid cells 2 (TREM2) signals affect the p38 MAPK-ULK1 process to control microglial activity and inflammation. Third, in Specific Aim III, I am working to determine the role of changing autophagy in microglial activity and inflammation in model animals. This is accomplished by determining the role of autophagy in inflammatory stimulus-induced brain inflammatory response and the role of p38 MAPK-ULK1 in microglial autophagy and inflammatory response in a rat AD model.
This study should help define a previously unrecognized mechanism for how autophagy and inflammation processes are connected. It should establish the role for this new regulatory process in microglial inflammatory response and in AD pathogenesis. Importantly, these results should advance our understanding how brain inflammation occurs in AD and help identify new potential therapeutic targets for intervention.
About the Researcher
Following the completion of my medical and master degree training from Southeast University School of Medicine (Nanjing, Jiangsu, China) and Zhejiang Academy of Medical Sciences (Hangzhou, Zhejiang, China), respectively, I received my PhD from Duke University Medical Center (Durham, NC, USA) after the successful completion of my thesis study with Dr. Wolfgang Joklik in the Department of Microbiology and Immunology. I then did my postdoctoral training in molecular and cellular neuroscience in Dr. Michael Greenberg’s laboratory at Harvard University Medical School/Children’s Hospital in Boston, MA. I joined the Department of Medicine at Brown University Medical School/Rhode Island Hospital in Providence, RI, in 1999, as an assistant professor and started my own independent research. I moved to the Departments of Pharmacology and Neurology at Emory University School of Medicine, Atlanta, GA, as an associate professor in 2005, and am now a full professor. My laboratory research focuses on the mechanisms of neuronal stress response and their roles in maintaining central nervous system homeostasis and in neurodegenerative disorders, including Alzheimer’s disease. My work has revealed the signaling networks critical for these processes.
The support by BrightFocus Foundation could not have come at a more critical time. With NIH support becoming more and more competitive, many good and promising ideas cannot be funded. The support from BrightFocus Foundation not only allows me to pursue a line of research that is not my traditional area of focus, but also affords me the ability to test new ideas more fully at an earlier stage. I greatly appreciate the support and thank the BrightFocus donors for making this possible.
First published on: July 20, 2016
Last modified on: June 30, 2019