Scleroderma Twin Study

描述（由申请方提供）：系统性硬化症（SSc;硬皮病）是一种病因不明的结缔组织疾病，与显著的发病率和死亡率相关。长期以来，人们一直认为SSc可能是由环境因素引起的，尽管这些环境因素尚未被确定。评估环境和遗传对疾病发展的影响的黄金标准是对双胞胎的研究。我们几年前进行的一项对SSc双胞胎的横断面研究显示，同卵（MZ）和异卵（DZ）双胞胎的疾病一致性约为5%。已发表的关于SSc家族性病例的研究，以及我们双胞胎研究的结果表明，SSc可能发生在具有遗传易感背景的个体中，这些个体暴露于适当的环境触发因素或通过获得性遗传变化。因此，我们在具体目标1中提出，使用双胞胎队列和一个大型SSc患者队列和匹配对照来确定可能与SSc相关的环境因素。由于表观遗传调控已成为介导基因表达和疾病表型表现的重要机制，因此设计了具体目标2来比较参与我们研究的双胞胎的DNA甲基化谱。最后，我们将探讨 环境因素对DNA甲基化的影响有针对性3.我们的研究结果将大大推进我们对SSc疾病发病机制的理解，为疾病的表观遗传机制提供新的见解，并确定环境因素与DNA甲基化改变之间的因果关系。我们的研究结果将推动该领域的进展，并为学员提供新的研究途径，以促进他们的研究，并允许他们建立自己的独立研究计划。这些学员将在整个奖励期间成为PI计划的不可或缺的参与者。主要研究者将指导年轻的医生科学家评估患者的SSc和健康双胞胎的无疾病情况，评估雷诺现象，获得知情同意，向患者和对照组发放问卷，使用临床样本，检查DNA甲基化谱，将匹兹堡大学硬皮病血清库和匹配的临床数据库应用于他们的研究项目，环境因素对DNA甲基化的影响分析。总之，这些方法将在流行病学，风险因素识别，环境医学和临床表观遗传学方面培训学员。该应用程序的指导目标还包括指导年轻的医生科学家在以患者为导向的研究，granecraft，手稿写作，负责任的研究行为和职业发展。PI作为优秀导师的声誉，加上匹兹堡大学的协作和支持环境，该机构的可用资源以及通过 CTSI和匹兹堡硬皮病中心的资源为吸引和培训成功的医生科学家提供了完美的环境。我们的成功将为临床研究人员提供一个管道，继续治疗患者和确定硬皮病及相关疾病的病因和治疗的使命。

DESCRIPTION (provided by applicant): Systemic sclerosis (SSc; Scleroderma) is a connective tissue disease of unknown etiology that is associated with significant morbidity and mortality. It has long been presumed that SSc likely results from environmental triggers, although these environmental insults have not been identified. The gold standard for assessing the role of environmental and inherited genetic effects on the development of a disease is the study of twins. A cross sectional study of twins with SSc we conducted several years ago showed a comparable concordance for disease of approximately 5% in monozygotic (MZ) and dizygotic (DZ) twins. Published research on familial cases of SSc, in conjunction with findings from our twin study, suggests that SSc likely develops in individuals with a genetically susceptible background upon exposure to appropriate environmental triggers or via acquired genetic changes. We therefore propose in specific aim 1 to identify environmental factors that may associate with SSc using the twin cohort and a large cohort of SSc patients and matched controls. Since epigenetic regulation has emerged as an important mechanism mediating gene expression and the manifestation of a disease phenotype, specific aim 2 is designed to compare the DNA methylation profile of twins participating in our study. Lastly, we will explore the effect of environmental factors on DNA methylation in specific aim 3. Our findings will significantly advance our understanding of disease pathogenesis in SSc, provide novel insights into epigenetic mechanisms underlying the disease, and identify a causal relationship between environmental factors and altered DNA methylation. Our findings will propel progress in the field and provide new avenues for research for mentees to facilitate their research and allow them to establish their own independent research programs. These mentees will be integral participants in the PI's program throughout the award period. The PI will mentor young physician scientists in the assessment of SSc in patients and the absence of disease in healthy twins, the evaluation of Raynaud phenomenon, obtaining informed consent, administration of questionnaire to patients and controls, use of clinical samples, the examination of DNA methylation profiles, the application of the University of Pittsburgh Scleroderma SerumBank and matching clinical Database to their research projects, and the analysis of environmental factors on DNA methylation. Together, these approaches will train the mentees in epidemiology, identification of risk factors, environmental medicine, and clinical epigenetics. The mentoring goals of this application also include mentoring young physician scientists in patient-oriented research, grantsmanship, manuscript writing, responsible conduct of research, and career development. The PI's reputation as an excellent mentor coupled with the collaborative and supportive environment at the University of Pittsburgh, the resources available at the institution and via the CTSI, and the resources of the Scleroderma Center of Pittsburgh, provide the perfect environment for attracting and training successful physician scientists. Our success will provide a pipeline of clinical investigators to continue the mission of treating patients and identifying te cause and cure for Scleroderma and related diseases.