Scleroderma Twin Study

描述(申请人提供)：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有关。长期以来，人们一直认为SSC可能是环境诱因的结果，尽管这些环境侮辱还没有被识别出来。评估环境和遗传遗传效应在疾病发展中的作用的金标准是对双胞胎的研究。我们几年前进行的一项双胞胎与SSC的横断面研究显示，同卵双胞胎(MZ)和异卵双胞胎(DZ)的疾病具有类似的一致性，约为5%。已发表的关于SSc家族性病例的研究，结合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人身上，暴露于适当的环境触发因素或通过获得性基因变化。因此，我们建议在特定的目标1中，使用双生子队列和大量的SSC患者和匹配的对照组来确定可能与SSC相关的环境因素。由于表观遗传调控已成为调节基因表达和疾病表型表现的重要机制，因此，我们设计了特殊目标2来比较参与我们研究的双胞胎的DNA甲基化情况。最后，我们将探讨其影响 我们的发现将极大地促进我们对SSC疾病发病机制的理解，为疾病的表观遗传学机制提供新的见解，并确定环境因素与DNA甲基化改变之间的因果关系。我们的发现将推动该领域的进步，并为被辅导者提供新的研究途径，以促进他们的研究，并允许他们建立自己的独立研究计划。在整个颁奖期内，这些受训者将成为PI项目中不可或缺的参与者。PI将指导年轻的内科科学家评估患者的SSc和健康双胞胎中没有疾病，评估雷诺现象，获得知情同意，向患者和对照管理问卷，使用临床样本，检查DNA甲基化情况，匹兹堡大学硬皮病血清库和匹配临床数据库的应用，他们的研究项目，以及环境因素对DNA甲基化的分析。综合起来，这些方法将对受训者进行流行病学、风险因素识别、环境医学和临床表观遗传学方面的培训。该应用程序的指导目标还包括指导年轻的内科科学家以患者为导向的研究、赠款精神、手稿写作、负责任的研究行为和职业发展。PI作为一名优秀导师的声誉，加上匹兹堡大学的协作和支持环境，该机构和通过 CTSI和匹兹堡硬皮病中心的资源为吸引和培训成功的内科科学家提供了完美的环境。我们的成功将提供一条临床研究人员的管道，继续治疗患者并确定硬皮病和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.