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LRRK2 and inflammasome pathway in Parkinson's disease

帕金森病中的 LRRK2 和炎症小体通路

基本信息

批准号：
10432114
负责人：
Christopher A Ross
金额：
$ 65.86万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
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/10432114
关键词：
Affect Animal Model Biological Biological Assay Blood Brain Cell Death Cells Cerebrospinal Fluid Chronic Disease Code Collaborations Crohn&apos s disease Development Disease Disease Progression Dose Encephalitis GTP Binding Genetic Guanosine Triphosphate Phosphohydrolases Human Immune Immune System Diseases Immunity In Vitro Induction of Apoptosis Infection Inflammasome Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Interleukin-1 beta Interleukin-18 Intervention Knock-in Knock-in Mouse Knock-out Knockout Mice LRRK2 gene Leprosy Link Lipopolysaccharides Maps Mediating Mediator of activation protein 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 Pharmacology 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 in vivo induced pluripotent stem cell innate immune function insight knock-down mutant nervous system disorder neuroinflammation novel overexpression potential biomarker protein expression receptor sensor targeted biomarker tool

项目摘要

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.

摘要： LRRK 2基因座编码LRRK 2（富含亮氨酸重复序列激酶2）蛋白，是糖尿病的主要风险因素。帕金森病（PD）和LRRK 2基因突变导致遗传性和散发性PD。有趣的是，LRRK 2基因座也赋予克罗恩病和麻风病的风险增加，并且LRRK 2是在免疫细胞、神经元和神经胶质中表达。我们最近发现LRRK 2与NOD样蛋白相互作用，受体（NLR）传感器家族蛋白（NLRP），NLRP 1和NLRP 3。NLRP蛋白是先天性免疫缺陷的关键介质。免疫，并且是炎性小体的组分。我们建议测试突变LRRK 2 与NLRP 3-和NLRP 1-炎性体相互作用并激活，导致小胶质细胞活化，导致PD病理学的神经变性。在目标1中，我们将表征LRRK 2与 NLRP 1和NLRP 3在体外和体内。在目标2中，我们将研究突变体LRRK 2是否激活NLRP 3 - 1。 infammasome在小胶质细胞活化中的作用，导致体外和体内的神经炎症和变性。在目的3，我们将检查突变LRRK 2是否激活神经元中的NLRP 1-炎性小体，导致神经变性这些研究将阐明LRRK 2相关炎性体通路的机制神经退化和免疫功能紊乱它们也可能对其他神经系统疾病产生更广泛的影响。与神经炎症有关的疾病。NLRP/LRRK 2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，并可能为疾病修饰的发展提供新的靶点。治疗策略因此，该项目有可能产生重大影响，并使那些遭受 PD和其他神经退行性疾病。