LRRK2 and inflammasome pathway in Parkinson's disease

帕金森病中的 LRRK2 和炎症小体通路

• 批准号: 10640900
• 负责人: Christopher A Ross
• 金额: $ 64.29万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10640900
• 关键词: Affect; Animal Model; Biological; Biological Assay; Blood; Brain; Cell Death; Cells; Cerebrospinal Fluid; Chronic Disease; Code; Collaborations; Crohn' s disease; Development; Disease; Disease Progression; Dose; Encephalitis; GTP Binding; Genes; Genetic; Guanosine Triphosphate Phosphohydrolases; Human; IL18 gene; Immune; Immune System Diseases; Immunity; In Vitro; Induction of Apoptosis; Infection; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Interleukin-1 beta; Intervention; Knock-in; Knock-in Mouse; Knock-out; Knockout Mice; LRRK2 gene; Leprosy; Link; Lipopolysaccharides; Maps; Mediating; Mediator; Microglia; Molecular; Mus; Mutation; Natural Immunity; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neuronal Injury; Neurons; Onset of illness; Parkinson Disease; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphotransferases; Pilot Projects; Point Mutation; Production; Property; Protein Family; Proteins; Risk; Risk Factors; Role; Signal Transduction; Small Interfering RNA; Testing; Therapeutic; Toxic effect; Transgenic Organisms; brain tissue; cytokine; design; dopaminergic neuron; gain of function; genetic approach; glial activation; in vivo; induced pluripotent stem cell; innate immune function; insight; knock-down; mutant; nervous system disorder; neuroinflammation; novel; overexpression; pharmacologic; potential biomarker; protein expression; receptor; sensor; sporadic Parkinson' s Disease; targeted biomarker; tool

Abstract: The LRRK2 locus, coding for the LRRK2 (Leucine Rich Repeat Kinase 2) protein, is a major risk factor for Parkinson’s disease (PD), and mutations in the LRRK2 gene contribute to both genetic and sporadic PD. Intriguingly, the LRRK2 locus also confers increased risk for Crohn’s disease and leprosy, and LRRK2 is expressed in immune cells, neurons and glia. We recently discovered that LRRK2 interacts with NOD-like receptor (NLR) sensor family proteins (NLRPs), NLRP1 and NLRP3. NLRP proteins are key mediators of innate immunity, and are components of inflammasomes. We propose to test the hypothesis that mutant LRRK2 interacts with and activates the NLRP3- and NLRP1-inflammasomes leading to microglial activation and neurodegeneration contributing to PD pathology. In Aim 1, we will characterize the interaction of LRRK2 with NLRP1 and NLRP3 in vitro and in vivo. In Aim 2, we will investigate whether mutant LRRK2 activates the NLRP3- infammasome in microglial activation, leading to neuroinflammation and degeneration in vitro and in vivo. In Aim3, we will examine whether mutant LRRK2 activates the NLRP1-inflammsome in neurons, resulting in neurodegeneration. These studies will elucidate mechanisms underlying LRRK2-linked inflammasome pathway in neurodegeneration and immune dysfunction. They may also have broader implications for other neurological diseases related to neuroinflammation. The understanding of NLRP/LRRK2-linked pathways in PD pathogenesis may reveal potential biomarkers, and may provide novel targets for development of disease-modifying therapeutic strategies. Thus, this project has the potential for significant impact, and benefits those suffering from PD and other neurodegenerative diseases.

抽象的： LRRK2 位点编码 LRRK2（富含亮氨酸重复激酶 2）蛋白，是以下疾病的主要危险因素： 帕金森病 (PD) 和 LRRK2 基因突变会导致遗传性和散发性 PD。 有趣的是，LRRK2 基因座也会增加克罗恩病和麻风病的风险，并且 LRRK2 我们最近发现 LRRK2 与 NOD 样相互作用。 受体 (NLR) 传感器家族蛋白 (NLRP)、NLRP1 和 NLRP3 蛋白是先天性的关键介质。 我们建议检验突变 LRRK2 的假设。 与 NLRP3 和 NLRP1 炎症小体相互作用并激活，导致小胶质细胞激活 在目标 1 中，我们将描述 LRRK2 与 PD 病理学的相互作用。 NLRP1 和 NLRP3 的体外和体内实验 在目标 2 中，我们将研究突变型 LRRK2 是否激活 NLRP3-。 小胶质细胞激活中的炎症小体，导致体外和体内的神经炎症和变性。 Aim3，我们将检查突变的 LRRK2 是否激活神经元中的 NLRP1 炎症体，从而导致 这些研究将阐明 LRRK2 相关炎症小体通路的机制。 它们还可能对其他神经系统疾病产生更广泛的影响。 与神经炎症相关的疾病的理解 NLRP/LRRK2 相关通路在 PD 发病机制中的作用。 可能揭示潜在的生物标志物，并可能为疾病缓解的开发提供新的靶标 因此，该项目有可能产生重大影响，并使那些患有此病的人受益。 PD 和其他神经退行性疾病。