RGS10 in microglia activation and dopaminergic neuron survival

RGS10 在小胶质细胞激活和多巴胺能神经元存活中的作用

基本信息

批准号：
8318226
负责人：
Maria de Lourdes Gamez Tansey
金额：
$ 33.23万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8318226
关键词：
Ablation Affect Age Aging Birth Brain CREB1 gene Cell Death Cell Nucleus Cells Cessation of life Chronic Clinical Complex Cytosol Data Development Dopaminergic Cell GTP-Binding Protein Regulators Gene Expression Genetic Transcription Goals Guanosine Triphosphate Phosphohydrolases Heterogeneity Human Immunologic Surveillance Individual Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Inflammatory disease of the intestine Knockout Mice Manuscripts Measures Microglia Midbrain structure Modeling Molecular Motor Cortex Mus Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Nuclear Outcome Output Oxidopamine Parkinson Disease Pathogenesis Peripheral Phenotype Predisposition Process Production Proteins Publishing RGS Proteins Regulation Risk Factors Rodent Model Role Sampling Second Messenger Systems Signal Pathway Signal Transduction Stimulus Substantia nigra structure Testing Toxic Environmental Substances Toxic effect Tumor Necrosis Factor-alpha Wild Type Mouse base cell type cytotoxicity dopaminergic neuron macrophage neuroinflammation neuron development neuron loss neuronal survival novel pars compacta prevent public health relevance research study response response to injury restoration second messenger transcription factor

项目摘要

DESCRIPTION (provided by applicant): Microglia are brain-resident macrophages responsible for immune surveillance. These cells become activated in response to injury, infection, environmental toxins, and other stimuli, thereby critically influencing neuronal survival and brain function. A wealth of clinical and experimental data implicate chronic microglia activation and overproduction of inflammatory mediators in the pathogenesis of Parkinson's disease (PD), the pathological hallmark of which is loss of ventral midbrain dopaminergic (DA) neurons that control output from motor cortex. However, the key molecular regulators of neuroinflammatory responses in the ventral midbrain have yet to be identified. The goals of this proposal are to investigate the role of Regulator of G-protein Signaling (RGS)-10, a GTPase Accelerating Protein (GAP) enriched in microglia, in neuroinflammatory responses that influence the vulnerability of nigral DA neurons to inflammation-induced degeneration. In Specific Aim 1 we will investigate the role of RGS10 in microglia activation and impact on survival of dopaminergic neurons using cell-based and rodent models. In Specific Aim 2, we will define the molecular mechanism and signaling pathways involved in RGS10-dependent regulation of activation responses and gene expression in microglia using cell-based models. In Specific Aim 3 we will investigate the extent to which aging and neurodegeneration affect mouse and human RGS10 expression in microglia and peripheral macrophages. Completion of the proposed experiments will provide new information regarding the function of RGS10 in microglia and in neuroinflammatory responses in the ventral midbrain and may reveal novel targets for development of new therapies to prevent or treat PD, the second most common neurodegenerative disorder in the U.S. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) is the second most common neurodegenerative disease in the U.S. affecting 1-2% of individuals over age 60. Inflammatory processes have been strongly implicated in the pathogenesis of PD. The proposed studies will determine the role of RGS10 in microglia activation responses in protecting dopaminergic neurons against inflammation-induced degeneration. Completion of the proposed experiments may reveal new targets for therapies to prevent or delay development of PD in humans.

描述（由申请人提供）：小胶质细胞是负责免疫监视的脑居民巨噬细胞。这些细胞因响应损伤，感染，环境毒素和其他刺激而被激活，从而严重影响神经元的生存和脑功能。大量的临床和实验数据暗示了慢性小胶质细胞激活和炎症介质在帕金森氏病（PD）中的炎症介体的过量生产，其病理标志是腹侧中脑多巴胺能（DA）神经元的丧失，这些神经元控制了来自摩托cortex的输出。然而，腹脑中脑神经炎症反应的关键分子调节剂尚未确定。该提案的目标是调查G蛋白信号传导（RGS）-10的调节剂的作用，即富含小胶质细胞的GTPase加速蛋白（GAP），在神经炎症反应中影响nigral da神经元对炎症诱导的变性的脆弱性。在特定目标1中，我们将使用基于细胞和啮齿动物模型来研究RGS10在小胶质细胞激活中的作用以及对多巴胺能神经元存活的影响。在特定目标2中，我们将使用基于细胞的模型来定义与小胶质细胞中RGS10依赖的激活反应调节和基因表达有关的分子机制和信号通路。在特定的目标3中，我们将研究小胶质细胞和外周巨噬细胞中的衰老和神经退行性影响小鼠和人RGS10的表达程度。提出的实验的完成将提供有关腹膜中脑中RGS10在小胶质细胞和神经炎症反应中功能的新信息，并可能揭示出开发新疗法的新靶标，以预防或治疗PD，这是美国第二大最常见的神经退行性疾病，这是美国第二大最常见的神经变性疾病。公共卫生相关性：帕金森氏病（PD）是美国第二常见的神经退行性疾病，影响了60岁以上的1-2％。炎症过程与PD的发病机理有很大的影响。拟议的研究将确定RGS10在保护多巴胺能神经元免受炎症引起的变性的小胶质细胞激活反应中的作用。拟议的实验的完成可能会揭示用于预防或延迟人类PD发展的新靶标。