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的临床和基础合作研究人员。安德森癌症中心和北大公共卫生学院（人类遗传学中心）提议建立硬皮病（系统性硬化症或SSc）研究转化中心或UTHCORT- SSc。主任将是Frank C. Arnett，医学博士和Maureen D. Mayes，医学博士，公共卫生硕士。SSc是一种致命的人类疾病，死亡率高，没有有效的治疗方法，其特征是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，然而，有证据表明遗传和环境因素都有影响。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）来了解SSc的发病机制，特别是遗传因素，以及SSc结局的预测因素，并将其转化为改善该疾病患者的医疗保健。提出2个临床转化研究项目和1个基础研究项目及2个核心项目：1)利用DNA微阵列、RNA沉默和单核苷酸多态性（SNP）关联研究，利用功能基因组学方法确定SSc成纤维细胞、全皮肤和外周血细胞中的基因及其分子通路；2)对三个种族（高加索人、非洲裔美国人和墨西哥裔美国人）疾病结局的潜在人口统计学、临床、自身抗体和遗传预测因子（包括微阵列）的大型研究；3)基础研究，包括上文#1所述的基因组方法，以及两种转基因小鼠纤维化模型(TGF（3)受体和结缔组织生长因子（CTGF）过表达者）与人SSc的比较；4)血液和组织处理核心，用于处理和储存来自SSc患者的pbc、皮肤活检和培养成纤维细胞；5)建立行政核心，促进th - cort - ssc的转化研究活动，并选择新的试点和可行性研究。

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.