Peripheral BDZ Receptor - Biomarker of Neurotoxicity

外周 BDZ 受体 - 神经毒性生物标志物

• 批准号: 10414054
• 负责人: Tomas R Guilarte
• 金额: $ 46.26万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10414054
• 关键词: Acute; Animals; Appearance; Astrocytes; Attention; Basic Science; Behavior; Behavioral; Benzodiazepine Receptor; Biological Markers; Brain; Brain Diseases; Brain Injuries; Catalytic Domain; Cell membrane; Cell surface; Cellular biology; Chemicals; Clinical; Clinical Research; Cytokine Gene; Disease Progression; Encephalitis; Endoplasmic Reticulum; Environmental Health; Enzymes; Equilibrium; Exposure to; Female; Flow Cytometry; Gene Deletion; Gene Expression; Gene Proteins; Glutathione; Goals; Health; Heme; Homeostasis; Human; Image; Injury; Knock-out; Knockout Mice; Knowledge; Laboratories; Ligands; Lipopolysaccharides; Measures; Mediating; Membrane; Microglia; Mitochondria; Molecular; Movement; Mus; NADPH Oxidase; Names; National Institute of Environmental Health Sciences; Nerve Degeneration; Nervous System Physiology; Neuroglia; Neurologic; Neurologic Effect; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Peripheral; Phagocytosis; Pharmacology; Physiologic pulse; Physiology; Play; Positron-Emission Tomography; Production; Proteins; Psyche structure; Reactive Nitrogen Species; Reactive Oxygen Species; Recovery; Research; Role; Steroid biosynthesis; Strategic Planning; Study Section; Techniques; Therapeutic; Validation; Wild Type Mouse; base; biological adaptation to stress; biological research; cell motility; cell type; clinical biomarkers; cytochrome b558; dimer; effectiveness evaluation; environmental chemical; imaging study; improved; insight; interest; male; neuroimaging marker; neuroinflammation; neuropathology; neurotoxic; neurotoxicity; novel; novel therapeutic intervention; pre-clinical; preclinical study; protein expression; protein protein interaction; receptor; response; sex; tert-Butylhydroperoxide; therapeutic effectiveness; virtual

Project Summary (Abstract): 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.

项目概述（摘要）：本研究的长期目标是了解