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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.

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