Center for Research Translation in Scleroderma

描述（由申请人提供）：德克萨斯大学休斯顿分校（UTH）医学院和UT-MD的合作临床和基础研究者。安德森癌症中心和UTH公共卫生学院（人类遗传学中心）提议建立硬皮病（系统性硬化症或SSc）或UTHCORT-SSc研究转化中心。导演是弗兰克·C。Arnett，医学博士和副主任莫琳·D·Mayes，MD，MPH. SSc是一种毁灭性的人类疾病，具有高死亡率，并且没有有效的治疗，其特征在于弥漫性皮肤和内脏纤维化和血管损伤。SSc的发病机制尚不清楚，但有证据表明遗传和环境影响。因此，UTHCORT-SSc的中心主题是使用分子方法（候选基因的SNP基因分型和DNA微阵列）来理解发病机制，特别是遗传因素，以及SSc结局的预测因子，并将其转化为改善这种疾病患者的医疗护理。本研究拟开展两个转化型临床研究项目和一个基础研究项目，并提出两个核心研究内容：1）利用DNA微阵列、RNA沉默和单核苷酸多态性（SNP）相关研究，在一个大型多种族SSc患者队列中，通过功能基因组学方法确定SSc成纤维细胞、整个皮肤和外周血细胞中的基因及其分子通路; 2）对潜在的人口统计学、临床、自身抗体和遗传预测因素进行大型研究（包括微阵列）的疾病结果在三个种族群体（高加索人，非洲裔美国人和墨西哥裔美国人）; 3）基础研究，包括上述#1中的基因组方法，并与两种转基因小鼠纤维化模型的人SSc进行比较（TGF β受体和结缔组织生长因子（CTGF）过表达者; 4）血液和组织处理核心，用于处理和储存来自SSc患者的PBMC、皮肤活组织检查和培养的成纤维细胞;和5）一个行政核心，以促进UTH-CORT-SSc转化研究活动和选择新的试点和可行性研究。 本文提出的研究将更好地了解SSc的基本发病机制和潜在有用的临床预测结果，这将导致更有针对性的治疗和/或疾病预防。 敷设总结：硬皮病（Scleroderma，SSc）是一种原因不明的破坏性疾病，其导致皮肤和内脏器官增厚，并且影响每10，000个美国人中的3个的高死亡率。在CORT中，将使用SSc患者和SSc小鼠模型的血液和皮肤活检来研究多个基因的复杂相互作用。其目的是找到导致疾病的细胞通路和中断它们的方法，从而为这种目前无法治愈的疾病提供新的治疗方法甚至预防方法。

DESCRIPTION (provided by applicant): The University of Texas-Houston (UTH) Medical School and collaborating clinical and basic investigators at the UT-M.D. Anderson Cancer Center and the UTH-School of Public Health (Human Genetics Center) propose to establish a Center of Research Translation in Scleroderma (systemic sclerosis or SSc) or UTHCORT- SSc. The Director will be Frank C. Arnett, M.D. and the Associate Director Maureen D. Mayes, MD, MPH. SSc is a devastating human disease with high mortality and no effective treatment characterized by diffuse cutaneous and visceral fibrosis and vascular damage. The pathogenesis of SSc is unknown, however, there is evidence for both genetic and environmental influences. Thus, the central theme of UTHCORT- SSc is the use of molecular approaches (SNP genotyping of candidate genes and DNA microarrays) to understanding pathogenetic mechanisms, especially genetic factors, and the predictors of outcomes in SSc and translating them into improved medical care for patients with this disease. Two translational clinical and one basic research projects and two cores are proposed, as follows: 1) A functional genomics approach to defining genes and their molecular pathways in SSc fibroblasts, whole skin and peripheral blood cells utilizing DNA microarrays, RNA silencing and single nucleotide polymorphisms (SNP) association studies in a large multiethnic cohort of SSc patients; 2) a large study of potential demographic, clinical, autoantibody and genetic predictors (including microarrays) of disease outcomes in three ethnic groups (Caucasians, African-Americans and Mexican-Americans); 3) basic investigations, including genomic methods as in #1 (above), and comparisons with human SSc of two transgenic murine models of fibrosis (TGF(3 receptor and connective tissue growth factor (CTGF) over expressers ; 4) a Blood and Tissue Processing Core to process and store PBCs, skin biopsies and cultured fibroblasts from SSc patients; and 5) an Administrative Core for facilitating UTH-CORT-SSc translational research activities and selecting novel Pilot and Feasibility studies. The studies proposed here will provide better understanding of both the fundamental pathogenetic mechanisms and potentially useful clinical predictors of outcome in SSc which will lead to more directed therapies and/or disease prevention. Lay summary: Scleroderma (SSc) is a devastating disease of unknown cause which causes thickening of the skin and internal organs and high mortality which affects 3 in 10,000 Americans. The complex interactions of multiple genes will be studied in this CORT using blood and skin biopsies from SSc patients and mouse models of SSc. The aims are to find the cellular pathways causing disease and means to interrupt them, thus leading to new treatments or even prevention for this currently untreatable disease.