Signaling events regulating microglial functions and activation phenotypes

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Microglia are the immune cells of brain, which they protect from pathogens. In addition, microglial phagocytosis activity, cytokine production, and trophic factor secretion regulate neuronal plasticity, the key phenomenon that allows brain to reorganize its neural connections in response to new situations. While modulated microglial activity is beneficial, dysregulated microglial actions can cause neuronal dysfunction and promote cognitive deficits and neuronal death. These opposite roles of microglia are feasible because of their diverse functions attributed to specific activation phenotypes. ******The long term objective of my research is to reveal the molecular mechanisms of microglial actions in pathogen elimination, bystander neuronal injury, synapse maintenance and neuronal plasticity. This insight will allow us to explore the role of microglia on higher brain function including learning, memory and cognition. To address my long-term goals, I propose to explore the following short term (5 years) objectives utilizing poly(ADP-ribose) polymerase-1 (PARP-1) as a proven tool to reveal additional aspects of microglial signaling events. ***1) Determine the role of PARP-1 in regulation of microglial activation phenotype switch.***2) Identify transcription factors related to microglial activation phenotype changes. ***3) Dissect the molecular basis of microglial phagocytosis types. ******The proposed studies will be performed in vitro and some key points will be confirmed in in vivo. We will use microglia targeting molecular tools that I recently created to manipulate expression and activity of PARP-1, which has been suggested to serve as a key regulator of microglial functions. Microglial PARP-1 activation promotes pro-inflammatory responses and uncontrolled neuronal phagocytosis. Microglial PARP-1 inhibition dampens immune responses, while still allowing pathogen elimination. ******Outcomes from this proposed program will provide detailed mechanistic information about regulation of microglial functions that span from pathogen elimination to neuronal synaptic remodeling. Such information will be readily incorporated into the fields of neuroimmunology and synaptic plasticity, but be of interest also for the broader field of neuroscience. During the course of this research program at least six highly qualified personnel (HQP) will obtain training in a broad spectrum of up to date technologies applicable to neuroscience and other disciplines. HQP will develop their skills in critical thinking, oral presentations, scientific writing, team building and networking. This training environment will prepare them for diverse careers in academia, industry or government. **