Elucidating the role of LRRK2 in the gastrointestinal manifestation of PD

阐明 LRRK2 在 PD 胃肠道表现中的作用

• 批准号: 10284435
• 负责人: WENFEI HAN
• 金额: $ 15.88万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 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/10284435
• 关键词: Adult; Animals; Attenuated; Behavioral; Biological; Biological Markers; Biopsy; Brain; Cells; Colon; Constipation; Data; Databases; Dependovirus; Deterioration; Development; Disease; Disease Progression; Disease model; Early Intervention; Enteral; Feces; Immune; Immune System Diseases; Immune signaling; Individual; Inflammation; Inflammatory Bowel Diseases; Intestines; LRRK2 gene; Lewy body pathology; Link; Lymphatic; Lymphatic System; Lymphocyte; Malabsorption Syndromes; Midbrain structure; Molecular; Motor; Motor Activity; Mus; Mutation; Neuraxis; Neurons; Organ; Outcome Study; Parkinson Disease; Parkinsonian Disorders; Pathology; Patients; Pattern; Peripheral; Phenotype; Play; Reporting; Ribosomal RNA; Risk; Role; Specificity; Substantia nigra structure; System; Techniques; Tissues; Transduction Gene; Transfection; Variant; Viral; Wild Type Mouse; Work; alpha synuclein; base; behavior test; behavioral phenotyping; brain pathway; cell motility; cell type; dopaminergic neuron; gastrointestinal; genetic analysis; grasp; gut microbiome; gut-brain axis; high risk; ileum; inflammatory disease of the intestine; intravenous injection; microbiome analysis; microbiome composition; motility disorder; motor deficit; motor symptom; mouse synuclein alpha; mutant; neural circuit; novel; overexpression; pre-clinical

Project Summary Previous findings suggest a biological link between Inflammatory bowel disease (IBD) and Parkinson’s Disease (PD). However, the exact mechanism potentially linking gut inflammation to PD progression remains unknown. Interestingly, PD and IBD are both linked to mutations in the LRRK2 gene; specifically, recent genetic analyses led by Project 3’s PI Peter linked the LRRK2 variant N2081D to increased risk for both PD and IBD. It is however unknown whether the LRRK2N2081D variation plays a role in the development of these progressive disorders. Accordingly, the overall aim of this project is to examine the role of LRRK2 in α-synuclein-induced pathologies in gut tissue and their potential spread to brain. The approach is based on assessing the effects of inducing α- synuclein overexpression in lymphocytes and ileum/colon enteric neurons of LRRK2N2081D mutants and their wild- type counterparts. To attain cell specificity, we will employ optimized (adeno-associated) viral delivery systems that enable efficient systemic and organ-specific gene transduction. We will employ these cutting-edge viral techniques to induce systemic α-synuclein overexpression in lymphocytes and local overexpression in ileum/colon enteric neurons in LRRK2N2081D mutants and wild-type mice. We will assess gut motility, motor deficits, stool-based biomarkers, gut microbiome composition, as well as endogenous mouse α-synuclein aggregation and spreading. Accordingly, our Specific Aims are (1) to assess the impact of LRRK2N2081D variants on systemic lymphocytes vs. local ileum /colon enteric neuron pS129-α-syn aggregation and pathology; (2) to examine the impact of LRRK2N2081D variants on stool-based biomarkers and gut microbiome composition upon lymphocytic and enteric α-synuclein overexpression; (3) to examine the impact of LRRK2N2081D variants on Parkinsonian behavioral and cellular phenotypes upon lymphocytic and enteric α-synuclein overexpression. We expect greater motor deterioration and α-synuclein aggregation in the brain of LRRK2 N2081D mutants upon enteric α-synuclein transfection. On the other hand, we expect attenuated brain pS129-α-syn invasion upon lymphocytic α-synuclein transfection. The outcome of these studies may reveal novel opportunities for early interventions in the course of PD progression.

项目摘要 以前的发现表明炎症性肠病(IBD)和帕金森病之间存在生物学联系 (Pd)。然而，可能将肠道炎症与PD进展联系起来的确切机制仍不清楚。 有趣的是，PD和IBD都与LRRK2基因突变有关；具体地说，最近的遗传分析 在项目3‘S的领导下，皮皮特将LRRK2变种N2081D与PD和IBD的风险增加联系在一起。然而，它是 尚不清楚LRRK2N2081D变异是否在这些进行性疾病的发展中起作用。 因此，这个项目的总体目标是研究LRRK2在α-突触核蛋白诱导的病理中的作用 在肠道组织和它们的潜在扩散到大脑。该方法的基础是评估诱导α的效果- 突变体LRRK2N2081D及其野生型LRRK2N2081D在淋巴细胞和回肠/结肠肠神经元中的过表达 键入对应物。为了获得细胞特异性，我们将使用优化的(腺相关的)病毒传递系统 这使得有效的系统性和器官特异性基因转导成为可能。我们将利用这些尖端的病毒 诱导淋巴细胞全身性α-突触核蛋白过度表达和局部过度表达的技术 LRRK2N2081D突变体和野生型小鼠的回肠/结肠肠神经元。我们将评估肠道运动，运动 缺陷、基于粪便的生物标记物、肠道微生物组组成以及内源性小鼠α-突触核蛋白 聚集和传播。因此，我们的具体目标是(1)评估LRRK2N2081D变异的影响 对系统淋巴细胞和回肠/结肠局部肠神经元pS129-α-syn聚集和病理的影响； 研究LRRK2N2081D变异对大便生物标志物和肠道微生物组组成的影响 淋巴细胞和肠道中α-Synuclein的过度表达；(3)检测LRRK2N2081D变异对 淋巴细胞和肠道α-突触核蛋白过度表达对帕金森病患者行为和细胞表型的影响。我们 预计LRRK2N2081D突变体在肠道时会出现更大的运动退化和脑内α-突触核蛋白聚集 α-突触核蛋白转染法。另一方面，我们预计脑部ps129-α-syn对淋巴细胞的侵袭减弱。 α-突触核蛋白转染法。这些研究的结果可能为早期干预提供新的机会。 帕金森病的进展过程。