Investigating the relationship of genetic, microbial, and intestinal inflammatory biomarkers in PD pathogenesis

帕金森病（Parkinson's disease，PD）是世界范围内第二大常见的神经退行性疾病。当前没有任何 现有的治疗改变了潜在的神经退行性过程，只有对症治疗才能 提高患者生活质量。这可能部分归因于不同的PD亚型需要 不同的治疗，表明对更有效的个性化治疗的大量未满足的需求， 关于疾病病因。遗传和炎症生物标志物的结合可能提供了一种途径， 解剖PD异质性。人们越来越认识到慢性炎症在发病机制中的作用 的PD。具体而言，炎症性肠病（IBD）患者PD的发生率增加， 肠道疾病，已经在世界范围内报道。我们先前的工作强烈暗示编码PD相关的LRRK 2 IBD发病机制中的突变。我们还表明，选择性LRRK 2抑制剂改善了 实验性结肠炎和炎性细胞因子TNF-α水平降低，这是IBD相关性结肠炎的标志。 炎症，在IBD患者的树突状细胞中。肠道炎症和PD之间的联系也是 肠道炎症和促炎性肠道微生物群组成的标志物升高， 这表明肠道免疫系统的信号通路失调可以解释PD患者的免疫功能。 对某些PD亚型的易感性。然而，即使减少炎症过程已经被证明是有效的， 建议作为PD的有希望的干预目标，尚未确定因果生物学途径， 用于开发新的或重新利用现有的药物靶点。因此，本研究的目的是检测 肠道炎症在PD发展中的作用程度，并根据 肠道免疫失调的遗传易感性水平。我们的具体目标是：1）确定 PD、IBD患者或对照组中肠道生物标志物与肠道微生物组多样性之间的关系 粪便钙卫蛋白是肠道炎症的敏感标志物， 2）询问α-突触核蛋白水平、LRRK 2表达和LRRK 2介导的 IBD、PD和对照患者肠组织中靶蛋白的磷酸化，以及3） 在发病年龄方面表征具有高遗传确定的炎症负荷的PD患者， 运动和非运动症状、疾病进展、对药物的反应和使用多基因治疗的合并症 在大型现有PD数据集中计算的各种肠道炎症状况的风险评分（PRS）。我们 将确定PD和免疫介导的疾病之间共享的生物学途径。拟议 研究将有助于更好地了解肠道炎症在PD发病机制中的作用。此外，他们将 帮助建立成功招募患者和样本采集基础设施， 合作指导，以支持旨在识别PD风险早期生物标志物的P50大规模研究， 确定PD亚型和开发新的治疗靶点。

Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide. Currently, no available therapies alter the underlying neurodegenerative process, and only symptomatic therapies can improve patient quality of life. This may be in part attributable to the fact that different PD subtypes require distinct therapies, indicating a substantial unmet need for more effective personalized therapies that are based on disease etiology. A combination of genetic and inflammatory biomarkers may offer an avenue toward the dissecting PD heterogeneity. There is growing appreciation for the role of chronic inflammation in pathogenesis of PD. Specifically, an increased incidence of PD in patients with inflammatory bowel disease (IBD), a chronic disease of the gut, has been reported world-wide. Our prior work strongly implicated coding PD-related LRRK2 mutations in the pathogenesis of IBD. We also showed that selective LRRK2 inhibitors have ameliorated experimental colitis and reduced inflammatory cytokine TNF-α levels, a hallmark of IBD-associated inflammation, in dendritic cells of IBD patients. The link between intestinal inflammation and PD is also endorsed by elevated markers of intestinal inflammation and pro-inflammatory gut microbiota composition in PD patients, suggesting that dysregulated signaling pathways of the gut immune system could explain the susceptibility to certain subtypes of PD. However, even though reducing inflammatory processes has been suggested as promising interventional goal for PD, no causal biological pathways have been identified to allow for developing novel, or repurposing existing, drug targets. Therefore, the goal of this study is to detect to what extent intestinal inflammation contributes to the development of PD and identify subtypes of PD based on the levels of genetic susceptibility to intestinal immune dysregulation. Our specific aims are: 1) To determine the relationship between intestinal biomarkers and gut microbiome diversity in patients with PD, IBD or controls by comparing fecal calprotectin, a sensitive marker of intestinal inflammation, and stool bacterial diversity between the disease and control groups; 2) Interrogate α-synuclein levels, LRRK2 expression and LRRK2-mediated phosphorylation of target protein in the intestinal tissue of patients with IBD, PD and controls, and 3) Characterize PD patients with high genetically-determined inflammatory burden in terms of their age of onset, motor and non-motor symptoms, disease progression, response to drugs, and comorbidities using polygenic risk scores (PRS) for various intestinal inflammatory conditions calculated in large existing PD datasets. We will identify the biological pathways shared between PD and immune-mediated diseases. The proposed studies will help better understand the role of intestinal inflammation in PD pathogenesis. In addition, they will help establish an infrastructure for successful patient recruitment and sample collection and formalize new collaborative directions to support large scale studies of P50 aimed at identifying early biomarkers of PD risk, determining PD subtypes, and developing new therapeutic targets.