Functional Genomics Approach to SSc Pathogenesis

硬皮病或系统性硬化症（SSc）是一种多系统疾病，具有高发病率和死亡率， 病因和发病机制尚不清楚。SSc的病理图片包括广泛的皮肤 以及内脏纤维化、闭塞性小血管疾病和自身免疫现象。越来越多的证据表明， SSc是一种复杂的异质性疾病，其中几个（或许多）基因 也可能与环境因素有关。在这项提案中，我们将使用功能基因组学或 系统生物学方法在鉴定易感性/表达中补充遗传关联研究 基因、遗传网络和分子通路参与SSc的发病机制。除了病例对照 在几个大型SSc队列中使用SNP基因分型进行的候选基因关联研究，疾病相关 使用SSc皮肤活检组织、培养的成纤维细胞的DNA微阵列的基因表达谱， 将使用新的建模方法来确定和分析外周血细胞（及其子集）。 此外，如此鉴定的重要途径中的选定基因将使用RNA沉默进行基因沉默。 干扰（RNAi），以确定其效果和潜在的治疗干预的相对优点 在SSc中。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，以更全面的分子机制的图片，其理解将 导致新的和更合理的/有针对性的方法来治疗，治愈或预防这种破坏性的疾病， 疾病 外行语言：这项研究的目的是更好地了解硬皮病的遗传原因，并确定 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” 技术，以确定这些途径，他们如何导致疾病，以及干扰可能会停止 过程这些研究将增加我们对硬皮病发病机制的认识， 更好的医疗、治疗或预防。

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.