Metaorganismal TMAO pathway driving scleroderma pathogenesis: novel gene-environment interaction paradigm and therapeutic target

项目摘要/摘要 系统性硬化症(SSC)是一种典型的纤维性疾病，几乎影响到每个器官。遗传和环境 这两个因素都会导致疾病。除了纤维化，血管损伤和肠道生物失调也很突出； 然而，这些不同的过程是如何由基因-环境相互作用管理的，以及它们是如何联系在一起的 两者在发病机制上的共同作用在很大程度上是未知的，排除了疾病修正疗法的发展。基于 来自我们实验室和其他实验室的引人注目的最新数据，我们现在为难以捉摸的基因提出一个新的范例- SSC中的环境相互作用将肠道微生物代谢与血管损伤和纤维化联系在一起，并开启了 创新疗法的大门：1)暴露在西方饮食中的肠道微生物群会产生三甲胺(TMA)， 在宿主中被含有黄素的单加氧酶转化为三甲胺N-氧化物(TMAO) (FMO3)。TMAO升高与内皮细胞损伤、纤维化细胞表型的促进有关，以及 组织纤维化；2)FMO3的遗传变异与SSC高度相关；以及3)表达 Fmo3在SSC皮肤成纤维细胞中显著上调。我们的假设是，富含胆碱的饮食是通过 化生体轴产生升高的TMAO，从而促进血管损伤和器官纤维化 内皮-间充质转化(EndoMT)等途径参与了SSC的发病机制。我们建议 可以通过选择性地抑制肠道TMA裂解酶这种微生物酶来减轻纤维化倾向 独家负责TMA的生成。这代表了一种独特的、变革性的治疗模式。 在前两年(R61阶段)，我们将确定是否以及如何依赖饮食的慢性TMAO升高 在不同的体内疾病模型和移植细胞中影响纤维化。然后我们将评估一个翻译上的- 相关的新型化合物选择性地抑制肠道中的TMA裂解酶，从而改变这些反应。我们会 确定内毒素是否是饮食相关的TMAO升高和血管相关的关键机制 损伤和纤维化。在第3年(R33阶段)，在实现我们预定义的里程碑后，我们将定义 FMO3在饮食诱导的纤维化倾向中的作用，并确定循环TMAO是否是一种潜在的诊断方法 在横断面和纵向研究中，SSC及其内分泌类型的预后生物标志物。这个项目 寻求验证一种全新的将环境/饮食和遗传风险联系起来的SSC范例(FMO3变体) 在一条作为SSc发病基础的代谢途径中，可以选择性地作为治疗的靶点。

PROJECT SUMMARY/ABSTRACT Systemic sclerosis (SSc) is a prototypic fibrotic illness affecting virtually every organ. Genetic and environmental factors both contribute to disease. In addition to fibrosis, vascular injury and gut dysbiosis are prominent; however, how these distinct processes are governed by gene-environment interactions, and how they are linked together in pathogenesis is largely unknown, precluding development of disease-modifying therapy. Based on remarkable recent data from our lab and others, we now propose a novel paradigm for the elusive gene- environment interaction in SSc that ties gut microbial metabolism to vascular injury and fibrosis and opens the door for innovative therapy: 1) gut microbiota exposed to a Western diet generate trimethylamine (TMA), which is converted in the host to trimethylamine N-oxide (TMAO) by the enzyme flavin-containing monooxygenase (FMO3). Elevated TMAO is associated with endothelial cell injury, promotion of fibrotic cellular phenotypes, and tissue fibrosis; 2) genetic variants of FMO3 show highly significant association with SSc; and 3) expression of FMO3 is significantly upregulated in SSc skin fibroblasts. Our hypothesis is that choline-rich diets via a metaorganismal axis generate elevated TMAO, which promotes vascular injury and organ fibrosis via endothelial-mesenchymal transition (endoMT) and other pathways implicated in SSc pathogenesis. We propose that the fibrotic propensity can be mitigated by selectively inhibiting gut TMA lyase, the microbial enzyme exclusively responsible for TMA generation. This represents a distinct and transformative treatment paradigm. During the first two years (R61 phase), we will determine if and how diet-dependent chronic TMAO elevation impacts fibrosis in distinct in vivo disease models and explanted cells. We will then evaluate if a translationally- relevant novel compound that selectively inhibits TMA lyase in the gut modifies these responses. We will determine whether endoMT represents a key mechanism linking diet-associated TMAO elevation and vascular injury and fibrosis. In Year 3 (R33 phase), undertaken upon achieving our predefined milestones, we will define the role of FMO3 in diet-induced fibrosis propensity, and determine if circulating TMAO is a potential diagnostic and prognostic biomarker of SSc and its endotypes in both cross-sectional and longitudinal studies. This project seeks to validate an entirely novel SSc paradigm that links the environment/diet and genetic risk (FMO3 variants) in a metaorganismal pathway that underlies SSc pathogenesis and can be selectively targeted for therapy.