): The long-term goal of this research is to understand the function(s) of Translocator Protein 18 kDa (TSPO) in glial cells, specifically in microglia. TSPO is a glial stress response protein that we have previously validated as a biomarker of brain injury and inflammation and it is currently used in preclinical and clinical Positron Emission Tomography (PET) imaging studies throughout the world. TSPO is a sensitive biomarker that is able to detect brain injury and neuroinflammation in a number of human neurodegenerative and mental conditions as well as in neurodegeneration induced by exposures to environmental chemicals. Furthermore, we are currently using TSPO as a biomarker of neurotoxicity to screen the neurotoxicity of chemicals for which there is currently no information on their potential to damage the brain. Despite the widespread use of TSPO in clinical and preclinical studies, there is a paucity of knowledge on the function(s) of TSPO in glial cells (microglia and astrocytes), the cell types that upregulate TSPO under neuropathological conditions. This proposal is aimed at understanding a novel interaction that we have discovered between TSPO and NADPH Oxidase (NOX2) in microglia that may provide important insights on modulation of brain reactive oxygen species (ROS) production and neuroinflammation. We present rigorously performed studies demonstrating the TSPO-NOX2 interaction and its modulation by microglia activation. There are three specific aims in the proposed research.
Specific aim 1 will examine the function of TSPO in primary microglia generated from wildtype and global TSPO knockout (TSPO-gKO) as well as microglia-specific conditional TSPO (mTSPO-cKO) mice.
Specific aim 2 will examine the subcellular localization and functional significance of the TSPO-NOX2 interaction in microglia. Finally, specific aim 3 will examine the neurological effects of TSPO deletion (global and microglia-specific) at the whole animal level. Combined, the proposed studies will generate new information on the function of TSPO in microglia. We will use state-of-the-art molecular and cellular techniques to understand the function of TSPO in microglia. A precise understanding of this novel TSPO-NOX2 interaction will provide new insights for devising therapeutics strategies for neurodegenerative conditions that involve neuroinflammation since NOX2 is involved in microglia-mediated neurodegeneration. This research topic is consistent with strategic objective 1 in advancing environmental health sciences basic biological research which is an integral part of the National Institute of Environmental Health Sciences strategic plan 2018-2023: Advancing Environmental Health Science, Improving Health 2.0.
Understanding the function of TSPO in microglia, specifically the newly identified TSPO- NOX2 interaction that we have discovered in our laboratory, will provide new information that will be valuable in regulating reactive oxygen species production in the brain. It is possible that TSPO ligands may be able to regulate the expression and activity of ROS producing NOX2 and mitigate ROS-induced injury in the brain. This could be a major breakthrough in mitigating brain inflammation, an important mechanism of neurodegeneration in many human neurological conditions.
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