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

帕金森氏病(PD)是全球第二常见的神经退行性疾病。目前，没有 现有的治疗方法可以改变潜在的神经退化过程，而且只有对症治疗才能 提高患者的生活质量。这可能部分归因于不同的PD亚型需要 不同的疗法，表明对更有效的个性化疗法的大量未得到满足的需求 关于疾病病因学。遗传和炎症性生物标记物的组合可能提供一条通往 剖析了钯的非均质性。人们越来越认识到慢性炎症在发病机制中的作用。 警局的。特别是，炎症性肠病(IBD)患者帕金森病的发病率增加，这是一种慢性疾病 肠道疾病，已在世界范围内得到报道。我们之前的工作强烈暗示了编码PD相关的LRRK2 IBD发病机制中的突变。我们还表明，选择性LRRK2抑制剂已经改善了 实验性结肠炎和炎性细胞因子肿瘤坏死因子-α水平降低是炎症性肠病的标志 炎症，在IBD患者的树突状细胞中。肠道炎症和帕金森病之间的联系也是 由肠道炎症标志物和促炎性肠道微生物区系组成升高支持 提示肠道免疫系统调节异常的信号通路可以解释 对某些帕金森病亚型的易感性。然而，尽管减少炎症过程一直是 被认为是帕金森病有希望的干预目标，目前还没有确定允许 用于开发新的或重新利用现有的药物靶点。因此，这项研究的目标是检测到 肠道炎症在帕金森病发生中的作用程度和根据以下指标确定帕金森病亚型 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 肠道生物标志物与PD、IBD患者及对照组肠道微生物群多样性的关系 粪便钙保护素，肠道炎症的敏感标志，和粪便细菌多样性的比较 2)检测α突触核蛋白水平、LRRK2的表达及其介导的LRRK2的表达 IBD、PD和正常对照组肠道组织中靶蛋白的磷酸化 根据帕金森病患者的发病年龄，确定其具有高遗传炎症负担的特征， 运动和非运动症状、疾病进展、对药物的反应以及使用多基因的共病 在现有大型PD数据集中计算的各种肠道炎症情况的风险评分(PR)。我们 将确定帕金森病和免疫介导性疾病之间共享的生物学途径。建议数 研究将有助于更好地了解肠道炎症在帕金森病发病机制中的作用。此外，他们还将 帮助建立成功招募患者和收集样本的基础设施，并正式确定新的 支持大规模P50研究的协作方向，旨在识别PD风险的早期生物标记物， 确定帕金森病亚型，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.