Functional Genomics Approach to SSc Pathogenesis

SSc 发病机制的功能基因组学方法

• 批准号: 7486187
• 负责人: FRANK C ARNETT
• 金额: $ 23.09万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7486187
• 关键词: Autoimmune Diseases; Biopsy; Biopsy Specimen; Blood; Blood Cells; Candidate Disease Gene; Complement; Complex; Cutaneous; DNA; DNA Microarray Chip; DNA Microarray format; Disease; Environmental Risk Factor; Etiology; Fibroblasts; Fibrosis; Gene Expression; Gene Silencing; Genes; Genetic; Genomics; Knowledge; Language; Lead; Medical; Methods; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Pathogenesis; Pathway interactions; Patients; Predisposition; Prevention; Process; RNA Interference; Relative (related person); SNP genotyping; Scleroderma; Skin; System; Systemic Scleroderma; Systems Biology; Technology; Therapeutic Intervention; Variant; Visceral; cohort; functional genomics; genetic association; mortality; novel; protein function

Scleroderma or systemic sclerosis (SSc) is a multi-system disease with high morbidity and mortality whose etiology and pathogenesis are unknown. The pathological picture in SSc includes widespread cutaneous and visceral fibrosis, obliterative small vessel disease, and autoimmune phenomena. Increasingly, evidence is being accumulated that SSc is a complex and heterogeneous disorder in which several (or many) genes interact, perhaps also with environmental factors. In this proposal, we will use a functional genomics or systems biology approach to complement genetic association studies in identifying susceptibility/expression genes, genetic networks and molecular pathways involved in the pathogenesis of SSc. In addition to casecontrol association studies of candidate genes using SNP genotyping in several large SSc cohorts, diseaserelated gene expression profiles using DNA microarrays of SSc skin biopsies, cultured fibroblasts, and peripheral blood cells (and subsets thereof) will be determined and analyzed using novel modeling methods. In addition, selected genes in important pathways so identified will undergo gene silencing using RNA interference (RNAi) in order to determine their effects and relative merits for potential therapeutic intervention in SSc. Such a "functional genomics" approach will integrate DNA variation, gene expression, and protein function/interactions into a more comprehensive picture of molecular mechanisms, whose understanding will lead to new and more rational/targeted approaches to therapy, cure, or prevention for this devastating disease. Lay language: This study aims to better understand the genetic causes of scleroderma and determine the genetic and cellular pathways contributing to its different complicating features. Blood and skin biopsy samples from patients with scleroderma will be studied using modern genetic typing and "genomic" technologies to identify such pathways, how they cause disease, and where interference may halt the process. Such studies will increase our knowledge of the mechanisms causing scleroderma and will lead to better medical treatments, cure or prevention.

硬皮病或系统性硬化症 (SSc) 是一种发病率和死亡率较高的多系统疾病， 病因和发病机制尚不清楚。 SSc 的病理表现包括广泛的皮肤 以及内脏纤维化、闭塞性小血管疾病和自身免疫现象。越来越多的证据 越来越多的证据表明，SSc 是一种复杂且异质的疾病，其中多个（或多个）基因 相互作用，也许还与环境因素相互作用。在本提案中，我们将使用功能基因组学或 系统生物学方法补充遗传关联研究以确定易感性/表达 SSc 发病机制涉及的基因、遗传网络和分子途径。除了病例对照 在几个大型 SSc 队列中使用 SNP 基因分型对候选基因进行关联研究，疾病相关 使用 SSc 皮肤活检、培养的成纤维细胞的 DNA 微阵列分析基因表达谱 将使用新颖的建模方法来确定和分析外周血细胞（及其子集）。 此外，如此确定的重要途径中的选定基因将使用 RNA 进行基因沉默 干扰（RNAi）以确定其效果和潜在治疗干预的相对优点 在SSc。这种“功能基因组学”方法将整合 DNA 变异、基因表达和蛋白质 功能/相互作用进入更全面的分子机制图景，其理解将 导致新的、更合理/有针对性的治疗、治愈或预防这种毁灭性的方法 疾病。 通俗易懂的语言：这项研究旨在更好地了解硬皮病的遗传原因并确定硬皮病的遗传因素。 遗传和细胞途径导致其不同的复杂特征。血液和皮肤活检 硬皮病患者的样本将使用现代基因分型和“基因组”进行研究 识别这些途径、它们如何引起疾病以及干扰可能在何处阻止疾病的技术 过程。此类研究将增加我们对引起硬皮病的机制的了解，并将导致 更好的医疗、治愈或预防。