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

摘要 项目1的目标是验证肠脑轴的假说以及LRRK2在肠脑调节中的作用 通过使用新的LRRK2基因小鼠模型研究Axis在帕金森病(PD)发病机制中的作用。帕金森已经很久了 与炎症性肠病(IBD)有关，以慢性炎症为特征，已知有两种 病情、克罗恩病(CD)和溃疡性结肠炎(UC)。最近发现的LRRK2变异体 PD和CD的风险增加为这两种疾病的联系提供了遗传学基础，并提高了 质疑它们是否具有相同的起源和疾病进展。LRRK2的G2019S最多 引起帕金森病的常见变种，其症状与特发性帕金森病难以区分。越来越多的证据 展示了LRRK2在免疫反应和外周免疫细胞感染中的作用。何以得病 然而，变异会影响LRRK2在炎症中的功能并导致疾病，目前仍不清楚。他的存在 LRRK2基因共有的PD和IBD风险变异的研究表明，LRRK2信号通路在 这两种慢性病的接口。因此，我们假设LRRK2的病理生理学研究 将有助于阐明IBD肠炎症的分子机制和肠脑轴。 警察。Pi Peter和Yue最近报道了LRRK2突变N2081D与CD和PD风险增加有关， 这与IBD患者帕金森病发病率较高的观察结果一致。为了验证病毒的致病作用 LRRK2N2081D在CD和PD中的作用，并检验了PD的肠-脑轴假说，我们建立了LrrK2N2081D敲击- 在(Ki)小鼠模型中。我们建议测试肠-脑轴的帕金森病的发病机制，并确定潜在的 通过对Lrrk2N2081D和Lrrk2G2019S小鼠的肠道和脑的特征进行研究。具体地说，我们将(1) 研究进行性炎症、联体核病和肠道和大脑的病理 化学诱导的结肠炎；(2)确定Lrrk2N2081D诱导的细胞类型特异性疾病的分子通路 和Lrrk2G2019S；(3)测定Lrrk2G2019S的异常激酶活性和特异性靶点 和Lrrk2N2081D在小鼠的肠道和大脑中。P20相的结果不仅有助于阐明分子 帕金森病的肠脑轴通路，但为LRRK2的测试奠定了分子基础和焦点假说 靶点作为未来P50应用中的致病因素。

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.