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

代谢有机TMAO途径驱动硬皮病发病机制：新的基因-环境相互作用范式和治疗靶点

• 批准号: 10672805
• 负责人: John Varga
• 金额: $ 34.11万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10672805
• 关键词: Affect; Attenuated; Automobile Driving; Biological Markers; Biology; Bleomycin; Blood Vessels; Cells; Choline; Chronic; Cross-Sectional Studies; Cutaneous sclerosis; Data; Databases; Development; Diet; Dietary Factors; Disease; Disease model; Disease susceptibility; Endothelial Cells; Endothelium; Environment; Environmental Risk Factor; Enzymes; Exposure to; FMO3; Fibroblasts; Fibrosis; Flavins; Gene Deletion; Generations; Genes; Genetic; Genetic Risk; Human; Innovative Therapy; Knowledge; Link; Long-Term Effects; Longitudinal Studies; Lyase; Mediating; Mesenchymal; Mesenchymal Stem Cells; Metabolism; Modeling; Molecular; Myofibroblast; Nutrient; Organ; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Process; Production; Prognostic Marker; Pulmonary Fibrosis; Research; Resolution; Role; Scleroderma; Series; Serum; Severities; Severity of illness; Systemic Scleroderma; Testing; Tissues; Transgenic Mice; Variant; base; cell injury; clinically relevant; coronary fibrosis; diagnostic biomarker; dietary; flavin-containing monooxygenase; gene environment interaction; genetic variant; gut dysbiosis; gut microbiome; gut microbiota; high reward; high risk; in vivo; inhibitor; innovation; kidney fibrosis; longitudinal analysis; microbial; mouse model; multidisciplinary; novel; novel strategies; response; senescence; skin fibrosis; targeted treatment; therapeutic target; tool; transcriptome; trimethylamine; trimethyloxamine; vascular injury; virtual; western diet

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.

项目摘要/摘要 全身性硬化症（SSC）是一种原型纤维化疾病，几乎影响每个器官。遗传和环境 因素都导致疾病。除纤维化外，血管损伤和肠道营养不良是突出的。 但是，这些不同的过程如何受到基因环境相互作用的控制，以及它们如何链接 发病机理中共同尚不清楚，从而排除了调整疾病的疗法的发展。基于 我们实验室和其他人的最新数据出色，我们现在为难以捉摸的基因提出了一种新颖的范式。 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起来，并打开 创新疗法的门：1）暴露于西方饮食的肠道菌群产生三甲胺（TMA） 通过含酶的单加氧酶在宿主中转换为三甲胺N-氧化物（TMAO） （FMO3）。 TMAO升高与内皮细胞损伤，促进纤维化细胞表型和 组织纤维化； 2）FMO3的遗传变异与SSC显示出非常显着的关联； 3）表达 在SSC皮肤成纤维细胞中，FMO3显着上调。我们的假设是通过A 元有机轴会产生升高的TMAO，从而促进血管损伤和器官纤维化 内皮 - 间质转变（内生）和其他与SSC发病机理有关的途径。我们建议 可以通过选择性抑制肠TMA裂解酶，微生物酶来减轻纤维化倾向。 专门负责TMA生成。这代表了一个独特的变革性治疗范式。 在头两年（R61阶段），我们将确定饮食依赖性慢性TMAO升高是如何以及如何 影响不同体内疾病模型和外植物细胞的纤维化。然后，我们将评估是否在翻译中 - 相关的新型化合物，在肠道中有选择地抑制TMA裂解酶会修饰这些反应。我们将 确定胚胎的凝血率是否代表关键机制，将饮食相关的TMAO升高和血管联系起来 损伤和纤维化。在第3年（R33阶段），在实现我们的预定义里程碑后进行，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是否是潜在的诊断 在横截面和纵向研究中，SSC及其内型的预后生物标志物。这个项目 试图验证一种完全新颖的SSC范式，该范式将环境/饮食和遗传风险联系起来（FMO3变体） 在基于SSC发病机理的元有机途径中，可以选择性地靶向治疗。