Role of TGF-Beta Genetic Variants in the Pathogenesis of Scleroderma

TGF-β 基因变异在硬皮病发病机制中的作用

• 批准号: 7267285
• 负责人: Boris Pasche
• 金额: $ 4.53万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7267285
• 关键词: Role; TGF; Beta; Genetic; Variants

Scleroderma/systemic sclerosis (SSc) is a chronic connective tissue disease of unknown etiology. The hallmark of established SSc is widespread tissue fibrosis affecting the skin and multiple internal organs. The pathogenesis of fibrosis in SSc is complex and remains poorly understood. Vascular injury and damage, and autoimmune responses appear to be coupled with aberrant activation of fibroblasts, resulting in progressive fibrosis. Transforming Growth Factor Beta (TGF-IJ) has emerged as a central mediator of initiation and/or propagation of the fibrotic response in involved tissues. Only few underpowered studies have examined genetic polymorphisms of the TGF-fc signaling axis in the pathogenesis of SSc. We propose to take advantage of the unique patient resources and substantial expertise available at Northwestern in SSc, TGFB biology and genetics to investigate the role of two common and functionally relevant variants of TGFB1 and its signaling receptor, TGFBR1, in a cohort of 200 well characterized patients with SSc and 400 age, gender and ethnic status matched healthy controls, in order to understand the role and contribution of genetic polymorphisms of the TGF-IJ signaling pathway in the development and progression of SSc. We have the following Specific Aims: Specific Aim 1: We will assess the association between the hypomorphic TGFBR1*6A allele and SSc and its two subsets, diffuse cutaneous SSc (dcSSc) and localized cutaneous SSc (IcSSc). We will also perform haplotype analysis of the TGFBR1 gene in cases and controls. Specific Aim 2: We will genotype cases and controls for the other functionally relevant variant of the TGF-p signaling pathway: TGFB1 T29C, which results in higher TGFB1 circulating level. We will also perform haplotype analysis of the TGFB1 gene in cases and controls. Exploratory Aims: As a first exploratory aim we will analyze gene-gene interactions between the two well characterized TGFBR1 and TGFB1 polymorphisms that affect TGF-P signaling. In this Aim we will explore the relationship between the variants and risk for scleroderma. This will allow us to determine the extent to which the overall level of TGF-p signaling, as predicted by combination of these two variants, will be associated with scleroderma risk. As a second exploratory aim, we will analyze the association between disease severity and TGFBR1 as well as TGFB1 genotypes.

硬皮病/系统性硬化症（SSc）是一种病因不明的慢性结缔组织疾病。这 已建立的 SSc 的标志是广泛的组织纤维化，影响皮肤和多个内脏器官。这 SSc 纤维化的发病机制很复杂，目前仍知之甚少。血管损伤和损伤，以及 自身免疫反应似乎与成纤维细胞的异常激活相结合，导致进行性 纤维化。转化生长因子β (TGF-IJ) 已成为启动和/或 相关组织中纤维化反应的传播。只有少数动力不足的研究检验了 SSc 发病机制中 TGF-fc 信号轴的遗传多态性。我们建议采取 充分利用西北大学在 SSc、TGFB 方面独特的患者资源和丰富的专业知识 生物学和遗传学研究 TGFB1 的两种常见且功能相关的变体的作用 及其信号受体 TGFBR1，在 200 名年龄 400 岁、特征明确的 SSc 患者组成的队列中， 性别和种族状况与健康对照相匹配，以便了解 TGF-IJ信号通路的遗传多态性在SSc的发生和进展中的作用。我们 有以下具体目标： 具体目标 1：我们将评估亚效性之间的关联 TGFBR1*6A 等位基因和 SSc 及其两个子集：弥漫性皮肤 SSc (dcSSc) 和局部皮肤 SSc (IcSSc)。我们还将对病例和对照中的 TGFBR1 基因进行单倍型分析。具体的 目标 2：我们将对 TGF-β 信号传导的其他功能相关变体的病例和对照进行基因分型 途径：TGFB1 T29C，导致较高的 TGFB1 循环水平。我们还将进行单倍型分析 对病例和对照中的 TGFB1 基因进行分析。探索性目标：作为第一个探索性目标，我们将 分析两个明确表征的 TGFBR1 和 TGFB1 多态性之间的基因-基因相互作用 影响 TGF-P 信号传导。在此目标中，我们将探讨变异与风险之间的关系 硬皮病。这将使我们能够确定 TGF-β 信号传导的总体水平的程度，如 通过这两种变异的组合预测，将与硬皮病风险相关。作为第二个 为了探索性目的，我们将分析疾病严重程度与 TGFBR1 以及 TGFB1 之间的关联 基因型。