Deciphering LRRK2 pathophysiology in mediating gut-brain axis of PD using novel genetic mouse models

使用新型遗传小鼠模型解读 LRRK2 介导 PD 肠脑轴的病理生理学

基本信息

批准号：
10284434
负责人：
Zhenyu Yue
金额：
$ 15.89万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2021-09-15 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10284434
关键词：
Acute Affect Autoimmune Diseases Autophagocytosis Biochemical Biological Markers Brain Brain Diseases Cell physiology Cells Chemicals Chronic Chronic Disease Clinical Colitis Constipation Crohn&apos s disease Data Disease Disease Progression Functional disorder Future Gender Genetic Goals Guanosine Triphosphate Phosphohydrolases Human Hyperactivity Idiopathic Parkinson Disease Immune Immune response Impairment In Vitro Incidence Infection Inflammation Inflammatory Bowel Diseases Investigation Knock-in Mouse LRRK2 gene Lead Link Lysosomes Mediating Molecular Molecular Disease Mus Outcome Parkinson Disease Pathogenesis Pathogenicity Pathology Pathway interactions Patients Peripheral Phase Phenotype Phosphorylation Phosphotransferases Reporting Risk Role Signal Pathway Substantia nigra structure Symptoms Testing Tissues Transgenic Mice Ulcerative Colitis Variant Weight cell type gastrointestinal genetic variant genome-wide gut-brain axis in vivo inflammatory disease of the intestine macrophage male monocyte mouse model mutant novel pleiotropism protein complex rab GTP-Binding Proteins risk variant single-cell RNA sequencing synucleinopathy trend

项目摘要

Summary The goal of Project 1 is to test the hypothesis of gut-brain axis and the role of LRRK2 in mediating the gut-brain axis in the pathogenesis of Parkinson’s disease (PD) by using novel LRRK2 genetic mouse models. PD has long been linked to inflammatory bowel disease (IBD), characterized by chronic inflammation and known for two conditions, Crohn’s disease (CD) and ulcerative colitis (UC). Recent identification of LRRK2 variants that increase the risk of both PD and CD has provided genetic basis for the link of the two disorders and raises a question whether they shared the same origin and disease progression. The G2019S of LRRK2 is the most common variant that causes PD with the symptoms indistinguishable from idiopathic PD. Increasing evidence demonstrates a role for LRRK2 in immune response and infection in peripheral immune cells. How disease variants affect LRRK2 functions in inflammation and cause disease, however, remains unknown. The presence of shared PD and IBD risk variants in the LRRK2 gene suggests that LRRK2 signaling pathways act at the interface of these two chronic diseases. Therefore, we hypothesize that investigation of LRRK2 pathophysiology will help elucidate the molecular mechanism underlying intestinal inflammation in IBD and the gut brain axis of PD. PI Peter and Yue recently reported LRRK2 variant N2081D associated with increased risk of CD and PD, consistent with the observations of a higher incidence of PD in IBD patients. To validate the pathogenic role of LRRK2N2081D in CD and PD and test the hypothesis of the gut-brain axis of PD, we established Lrrk2N2081D knock- in (KI) mouse model. We propose to test gut-brain axis for PD pathogenesis and determine the underlying mechanism by characterizing the guts and brain of Lrrk2N2081D and Lrrk2G2019S mice. Specifically, we will (1) investigate progressive inflammation, synucleinopathies and pathologies in the gut and brain following chemically induced colitis; (2) determine cell-type specific disease molecular pathways induced by Lrrk2N2081D and Lrrk2G2019S in mouse guts and brains; (3) determine aberrant kinase activity and specific targets of Lrrk2G2019S and Lrrk2N2081D in mouse guts and brains. The outcome of P20 phase will not only help illuminate the molecular pathways of gut brain axis of PD, but establish the molecular basis and focused hypothesis for the test of LRRK2 targets as disease causative factors in the future P50 application.

概括项目1的目标是检验肠-脑轴的假设以及LRRK2在介导肠-脑中的作用通过使用新型 LRRK2 基因小鼠模型，我们长期以来一直在研究帕金森病 (PD) 发病机制中的轴。与炎症性肠病（IBD）有关，其特征是慢性炎症，已知有两种最近鉴定出 LRRK2 变异体，包括克罗恩病 (CD) 和溃疡性结肠炎 (UC)。增加 PD 和 CD 的风险为这两种疾病的联系提供了遗传基础，并提出了质疑它们是否具有相同的起源和疾病进展。LRRK2 的 G2019S 是最重要的。导致 PD 的常见变异，其症状与特发性 PD 难以区分。证明了 LRRK2 在免疫反应和外周免疫细胞感染中的作用。然而，变异影响 LRRK2 在炎症中的功能并导致疾病，其存在仍然未知。 LRRK2 基因中共有的 PD 和 IBD 风险变异表明 LRRK2 信号通路作用于因此，我们正在研究 LRRK2 的病理生理学。将有助于阐明 IBD 肠道炎症和肠脑轴的分子机制 PD。PI Peter 和 Yue 最近报道了 LRRK2 变异 N2081D 与 CD 和 PD 风险增加相关。与 IBD 患者 PD 发病率较高的观察结果一致，以验证其致病作用。 LRRK2N2081D 在 CD 和 PD 中的作用并检验 PD 肠脑轴的假设，我们建立了 Lrrk2N2081D 敲除在 (KI) 小鼠模型中，我们建议测试肠脑轴的 PD 发病机制并确定潜在的机制。通过表征 Lrrk2N2081D 和 Lrrk2G2019S 小鼠的肠道和大脑，具体来说，我们将 (1) 研究肠道和大脑中进行性炎症、突触核蛋白病和病理学化学诱导的结肠炎；（2）确定Lrrk2N2081D诱导的细胞类型特异性疾病分子通路和Lrrk2G2019S在小鼠肠道和大脑中的作用；（3）确定Lrrk2G2019S的异常激酶活性和特定靶标小鼠肠道和大脑中的 Lrrk2N2081D P20 期的结果不仅有助于阐明分子机制。 PD 肠脑轴通路，但为 LRRK2 测试建立分子基础和重点假设未来P50应用中将目标作为疾病致病因素。