Peripheral BDZ Receptor - Biomarker of Neurotoxicity

外周 BDZ 受体 - 神经毒性生物标志物

• 批准号: 9817320
• 负责人: Tomas R Guilarte
• 金额: $ 46.23万
• 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/9817320
• 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; base; biological adaptation to stress; biological research; cell motility; cell type; clinical biomarkers; cytochrome b558; dimer; 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.

项目摘要（摘要）：这项研究的长期目标是了解 胶质细胞中的转运蛋白18 kDa（TSPO），特别是小胶质细胞。 TSPO是神经胶质应力响应 我们以前已证实是脑损伤和炎症的生物标志物的蛋白质，目前是 用于临床前和临床正电子发射断层扫描（PET）成像研究。 TSPO是一种敏感的生物标志物，能够检测许多人类的脑损伤和神经炎症 神经退行性和精神状况以及在暴露于 环境化学品。此外，我们目前正在使用TSPO作为神经毒性的生物标志物进行筛查 目前尚无有关其损害大脑潜力的化学物质的神经毒性。 尽管TSPO在临床和临床前研究中广泛使用，但关于该研究的知识很少 TSPO在神经胶质细胞（小胶质细胞和星形胶质细胞）中的功能，在下调TSPO的细胞类型 神经病理条件。该提议旨在理解我们有的新颖互动 在小胶质细胞中发现的TSPO和NADPH氧化酶（NOX2）之间，可能会提供有关重要见解的 调节大脑活性氧（ROS）产生和神经炎症。我们严格介绍 进行了研究，证明了TSPO-NOX2相互作用及其通过小胶质细胞激活的调节。那里 在拟议的研究中是三个具体目标。特定的目标1将检查TSPO在初级中的功能 由Wildtype和全球TSPO敲除（TSPO-GKO）以及小胶质细胞特异性产生的小胶质细胞 有条件的TSPO（MTSPO-CKO）小鼠。特定目标2将检查亚细胞定位和功能 小胶质细胞中TSPO-Nox2相互作用的重要性。最后，特定目标3将检查神经系统 TSPO缺失（全球和小胶质细胞特异性）在整个动物水平上的影响。合并，提议 研究将生成有关小胶质细胞中TSPO功能的新信息。我们将使用最先进的 分子和细胞技术了解TSPO在小胶质细胞中的功能。对 这种新颖的TSPO-Nox2相互作用将为设计治疗策略提供新的见解 由于NOX2参与小胶质细胞介导的，涉及神经炎症的神经退行性疾病 神经变性。该研究主题与战略目标1一致，以提高环境 健康科学基础生物学研究是美国国家环境研究所不可或缺的一部分 健康科学战略计划2018-2023：推进环境健康科学，改善健康2.0。