(Provided by the applicant) Abstract: The proposal addresses the poorly explored problem of microglia regulation by neurons. Activation of microglia is at the core of brain homeostasis, where microglia cells are involved in neuronal surveillance, as well as in immune defense against pathogens. We hypothesize that such cellular dynamics that shape brain function in health and disease require microglia tuning to the specific functions of highly specialized neurons in distinct brain areas. Our plans include investigations of spatial microglia diversity and its developmental mechanisms. Using methods of mouse genetics, we will access the possibility of microglia ""mimicry"" of its neuronal environment and its role in the regulation of microglia-mediated inflammatory response. In a complementary set of experiments, we will address the role of neuronal activity on microglia function and inflammatory gene activation. Our proposal has far reaching consequences for understanding of the role of microglia-neuron interaction in the regulation of inflammatory responses in the brain. The proposed work establishes deep connections between the disparate fields of neuroscience, cell differentiation, lineage plasticity and innate immunity. Thus, it will generate a new framework for understanding of the microglia-neuron interaction with fundamental implications for how we understand and control microglia function, especially within the context of neurodegenerative diseases. Public Health Relevance: The proposed research addresses a poorly understood mechanism of microglia -neuron interaction and its role in microglia-mediated inflammatory responses. Beyond the fundamental basic science implications, our work has the potential of revolutionizing strategies to study the mechanisms of neurodegeneration and its treatment. Our findings will provide a foundation for the development of new approaches for treatment of inflammation associated neurodegenerative disease such as Parkinson's, Huntington's, and Alzheimer disease.
|Cholewa-Waclaw, Justyna; Bird, Adrian; von Schimmelmann, Melanie et al. (2016) The Role of Epigenetic Mechanisms in the Regulation of Gene Expression in the Nervous System. J Neurosci 36:11427-11434|
|Hansen, Thomas B; VenÃ¸, Morten T; Jensen, Trine I et al. (2016) Argonaute-associated short introns are a novel class of gene regulators. Nat Commun 7:11538|
|von Schimmelmann, Melanie; Feinberg, Philip A; Sullivan, Josefa M et al. (2016) Polycomb repressive complex 2 (PRC2) silences genes responsible for neurodegeneration. Nat Neurosci 19:1321-30|
|Sullivan, Josefa M; Badimon, Ana; Schaefer, Uwe et al. (2015) Autism-like syndrome is induced by pharmacological suppression of BET proteins in young mice. J Exp Med 212:1771-81|
|Gao, Zhonghua; Lee, Pedro; Stafford, James M et al. (2014) An AUTS2-Polycomb complex activates gene expression in the CNS. Nature 516:349-54|
|Maze, Ian; Chaudhury, Dipesh; Dietz, David M et al. (2014) G9a influences neuronal subtype specification in striatum. Nat Neurosci 17:533-9|
|Tan, Chan Lek; Plotkin, Joshua L; VenÃ¸, Morten T et al. (2013) MicroRNA-128 governs neuronal excitability and motor behavior in mice. Science 342:1254-8|