Alpha-synuclein regulates microglial activation through lipid mediators

α-突触核蛋白通过脂质介质调节小胶质细胞活化

• 批准号: 7531702
• 负责人: ERIC James MURPHY
• 金额: $ 17.72万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7531702
• 关键词: Address; Affect; Amino Acids; Anti-Inflammatory Agents; Anti-inflammatory; Arachidonic Acids; Back; Brain; Cellular biology; Collaborations; Comb animal structure; Condition; Cultured Cells; Drug Formulations; Elderly; Event; Fatty Acids; Foundations; Functional disorder; Human; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Investigation; Ischemia; Kinetics; Knockout Mice; Laboratories; Lecithin; Link; Lipids; Mediating; Metabolism; Microglia; Modeling; Mus; Neurodegenerative Disorders; Numbers; Palmitic Acids; Parkinson Disease; Pathway interactions; Phenotype; Phosphatidic Acid; Phospholipase A2; Phospholipase D; Phospholipids; Physiology; Positioning Attribute; Prostaglandin Production; Prostaglandins; Proteins; Public Health; Regulation; Regulatory Pathway; Reporting; Research; Role; Signal Pathway; Signal Transduction; Stimulus; Testing; United States; Work; alpha synuclein; cytokine; expectation; experience; in vivo; innovation; insight; lipid mediator; lipid metabolism; mutant; neuroinflammation; novel; research study; response; synuclein; uptake

DESCRIPTION (provided by applicant): Parkinson's disease (PD) affects nearly 3% of individuals over the age of 65 and is the second most common neurodegenerative disease in the United States. Recently, there is an increasing appreciation for the role of inflammation and microglia in the progression of PD. 1-Synuclein is a widely distributed 140 amino acid protein in brain associated with PD and other neurodegenerative disorders, but its role in brain physiology is poorly understood. There is ample evidence, by us and others, which demonstrates that 1-synuclein has a profound impact on lipid-mediated signal transduction and on brain lipid metabolism. Lipid-mediated signaling is a critical component of the regulatory pathway for microglial activation; however, the role of 1-synuclein in modulating microglia activation state via the regulation of lipid-mediated signal transduction is poorly defined. This is important because we have recently discovered a novel link between 1-synuclein and microglial activation state. We will use two complimentary approaches in this proposal to address the role of 1-synuclein in neuroinflammatory response via its regulation of these lipid-mediated signaling pathways by using cultured microglia to determine mechanisms underlying this aberrant phenotype and extending these observations to the intact mouse subjected to neuroinflammatory insult. Understanding how 1-synuclein and its mutant forms affects microglial activation will offer insight into the pathophysiology of the inflammatory response in PD. We will address our Central Hypothesis that 1-synuclein expression modulates microglia activation by regulating multiple lipid-mediated signaling pathways by completion of the following specific aims: Specific Aim 1: Determine the extent that wt and A53T 1-synuclein expression modulates lipid mediated microglial activation Specific Aim 2: Resolve the extent to which wt and A53T 1-synuclein expression impacts lipid mediated signaling and microglial activation in vivo The proposed work is innovative because it examines a novel function of 1-synuclein and its mutant form (A53T) in regulating microglial activation through its ability to modulate cellular lipid metabolism. It is our expectation that these results will identify a key role for 1-synuclein in facilitating prostaglandin formation, PLD "and PLA2 activity, thereby regulating downstream lipid metabolism and microglial activation, both in cultured cells and in vivo. These results will be significant because they will demonstrate a pivotal role for 1-synuclein "in regulating microglial activation and thus brain inflammatory response. This will provide the fundamental foundation required to address the role that 1-synuclein and its mutant forms have in brain inflammatory "response, extending our understanding of how 1-synuclein modulates cellular lipid metabolism, thereby impacting neurodegenerative disease pathophysiology. PUBLIC HEALTH RELEVANCE The relevance of our proposed work is that it examines a novel function of 1-synuclein in regulating brain neuroinflammatory response through its ability to modulate lipid-mediated microglial activation pathways. This is important because of: 1). the poorly defined function of 1-synuclein in the brain; 2). the association of 1- synuclein with a large number of neurodegenerative diseases; and 3). the known association of inflammatory response in these neurodegenerative diseases. Results from this project will be significant because they will demonstrate a pivotal role for 1-synuclein in regulating brain neuroinflammatory response, extending our understanding of how 1-synuclein modulates cellular lipid metabolism, thereby increasing our understanding of how 1-synuclein impacts neurodegenerative disease pathophysiology.

描述（由申请人提供）：帕金森病 (PD) 影响近 3% 的 65 岁以上人群，是美国第二大常见的神经退行性疾病。最近，人们越来越认识到炎症和小胶质细胞在帕金森病进展中的作用。 1-突触核蛋白是大脑中广泛分布的 140 个氨基酸蛋白，与 PD 和其他神经退行性疾病相关，但其在大脑生理学中的作用知之甚少。我们和其他人有充分的证据表明 1-突触核蛋白对脂质介导的信号转导和脑脂质代谢具有深远的影响。脂质介导的信号传导是小胶质细胞激活调节途径的关键组成部分；然而，1-突触核蛋白通过调节脂质介导的信号转导来调节小胶质细胞激活状态的作用尚不清楚。这很重要，因为我们最近发现了 1-突触核蛋白和小胶质细胞激活状态之间的新联系。我们将在本提案中使用两种互补的方法，通过使用培养的小胶质细胞来调节这些脂质介导的信号通路来解决 1-突触核蛋白在神经炎症反应中的作用，以确定这种异常表型的机制，并将这些观察结果扩展到遭受神经炎症损伤的完整小鼠。了解 1-突触核蛋白及其突变形式如何影响小胶质细胞激活将有助于深入了解 PD 炎症反应的病理生理学。我们将通过完成以下具体目标来解决我们的中心假设，即 1-突触核蛋白表达通过调节多种脂质介导的信号传导途径来调节小胶质细胞活化： 具体目标 1：确定 wt 和 A53T 1-突触核蛋白表达调节脂质介导的小胶质细胞活化的程度 具体目标 2：解决 wt 和 A53T 1-突触核蛋白表达影响脂质的程度 体内介导的信号传导和小胶质细胞激活这项工作具有创新性，因为它研究了 1-突触核蛋白及其突变体 (A53T) 通过其调节细胞脂质代谢的能力来调节小胶质细胞激活的新功能。我们期望这些结果将确定 1-突触核蛋白在促进前列腺素形成、PLD 和 PLA2 活性中的关键作用，从而在培养细胞和体内调节下游脂质代谢和小胶质细胞活化。这些结果将具有重要意义，因为它们将证明 1-突触核蛋白在调节小胶质细胞活化和脑炎症中发挥关键作用 回复。这将为解决 1-突触核蛋白及其突变形式在脑炎症“反应中的作用”提供所需的基础，扩展我们对 1-突触核蛋白如何调节细胞脂质代谢，从而影响神经退行性疾病病理生理学的理解。 公共健康相关性 我们提出的工作的相关性在于，它检查了 1-突触核蛋白在调节脑神经炎症中的新功能 通过其调节脂质介导的小胶质细胞激活途径的能力来响应。这很重要，因为：1）。 1-突触核蛋白在大脑中的功能定义不明确； 2）。 1-突触核蛋白与大量神经退行性疾病的关联；和3）。这些神经退行性疾病中炎症反应的已知关联。该项目的成果将意义重大，因为它们将发挥关键作用 1-突触核蛋白在调节大脑神经炎症反应中的作用，扩展了我们对 1-突触核蛋白如何调节细胞脂质代谢的理解，从而增加了我们对 1-突触核蛋白如何影响神经退行性疾病病理生理学的理解。