Peripheral BDZ Receptor - Biomarker of Neurotoxicity

外周 BDZ 受体 - 神经毒性生物标志物

• 批准号: 10020410
• 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/10020410
• 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.

项目概要（摘要）：本研究的长期目标是了解 在神经胶质细胞，特别是小神经胶质细胞中的转运蛋白18 kDa（TSPO）。TSPO是一种神经胶质应激反应， 我们之前已经验证了这种蛋白质是脑损伤和炎症的生物标志物，目前它是 用于全世界的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，能够检测许多人的脑损伤和神经炎症。 神经变性和精神状况以及暴露于 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来筛选 化学品的神经毒性，目前没有关于其可能损害大脑的信息。 尽管TSPO在临床和临床前研究中广泛使用，但关于TSPO的应用的知识仍然很少。 TSPO在神经胶质细胞（小神经胶质细胞和星形胶质细胞）中的功能，在神经胶质细胞（小神经胶质细胞和星形胶质细胞）中上调TSPO的细胞类型， 神经病理状况这个提议的目的是为了理解一种新的相互作用， 在小胶质细胞中发现TSPO和NADPH氧化酶（NOX 2）之间的关系，这可能为研究 调节脑活性氧（ROS）的产生和神经炎症。我们严格呈现 进行了证明TSPO-NOX 2相互作用及其通过小胶质细胞活化的调节的研究。那里 在拟议的研究中有三个具体目标。具体目标1将检查TSPO在小学中的功能 由野生型和整体TSPO敲除（TSPO-gKO）产生的小胶质细胞以及小胶质细胞特异性 条件性TSPO（mTSPO-cKO）小鼠。具体目标2将检查亚细胞定位和功能 TSPO-NOX 2相互作用在小胶质细胞中的意义。最后，具体目标3将检查神经系统 在整个动物水平上TSPO缺失（整体和小胶质细胞特异性）的影响。合并后，拟议的 这些研究将产生关于TSPO在小胶质细胞中的功能的新信息。我们将使用最先进的 分子和细胞技术来了解TSPO在小胶质细胞中的功能。准确了解 这种新的TSPO-NOX 2相互作用将为设计治疗策略提供新的见解， 涉及神经炎症的神经退行性疾病，因为NOX 2参与小胶质细胞介导的炎症反应。 神经变性本研究课题与推进环境保护的战略目标1相一致 健康科学基础生物学研究是国家环境研究所的一个组成部分， 健康科学战略计划2018-2023：推进环境健康科学，改善健康2.0。