Scleroderma Twin Study and analysis of Estrogen in patients with dcSSc

摘要 系统性硬化症(SSC)是一种病因不明的结缔组织病。 发病率和死亡率都很高。长期以来，人们一直认为SSC可能是由环境因素引起的 触发因素，尽管这些对环境的侮辱尚未确定。评估角色的黄金标准 环境和遗传基因对疾病发展的影响的研究是对双胞胎的研究。十字勋章 我们几年前对双胞胎和SSc进行的横断面研究显示， 同卵双胞胎(MZ)和异卵双胞胎(DZ)的发病率约为5%。我们建议进行后续行动 确定疾病、ANA状态和自身抗体纵向一致性的双生子队列研究 现身。由于表观遗传调控已成为调节基因表达的重要机制 以及一种疾病表型的表现，我们还将比较双胞胎的DNA甲基化情况 纵向的。我们最近发现的导致SSc皮肤纤维化的因素之一是雌激素。我们的发现表明 弥漫性皮肤(DC)SSc高加索患者雌激素水平升高 与雌激素水平升高相关的疾病特征。因为DcSSc在非裔美国人中更为严重 (Aa)，我们现在建议测量绝经后aa女性和同龄男性的雌激素水平。 DcSSc和识别与疾病的临床特征相关。我们的发现将大大推进我们的 对SSc疾病发病机制的理解，推动了该领域的进步，并提供了重要的新途径 为受训者进行研究，以促进他们的研究并允许他们建立自己的独立研究 程序。在整个获奖期内，这些学员将成为我项目中不可或缺的参与者。我会指导你的 初级医生调查员在评估患者的SSc和健康双胞胎中没有疾病时， 评估雷诺现象、检测自身抗体、获得知情同意、储存和使用 临床样本，DNA甲基化图谱的检查，雌激素的测量，以及 与临床变量的关系。该应用程序的指导目标还包括指导初级临床医生 研究人员以病人为中心，勇于担当，撰写手稿，负责任地开展研究， 创业创新、事业发展。我作为一名优秀导师的声誉加上 南卡罗来纳医科大学的协作和支持环境，可用的资源 在该机构和通过CTSA，以及风湿科P30 CCCR的资源，提供 吸引和培训成功的临床医生研究人员的完美环境。我的最终目标是确保 训练有素的临床研究人员队伍，他们将继续治疗病人和识别 硬皮病及相关疾病的病因和治疗。

ABSTRACT 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. We propose to conduct a follow-up study of the twin cohort to determine longitudinal concordance for disease, ANA status, and autoantibody presence. Since epigenetic regulation has emerged as an important mechanism mediating gene expression and the manifestation of a disease phenotype, we will also compare the DNA methylation profile of twins longitudinally. One of the factors we recently implicated in dermal fibrosis in SSc is estrogen. Our findings show that estrogen levels are elevated in Caucasian patients with diffuse cutaneous (dc)SSc and identified clinical features of disease associated with elevated estrogen levels. Since dcSSc is more severe in African Americans (AA), we now propose to measure estrogen levels in post-menopausal AA women and men of similar age with dcSSc and identify correlates with clinical features of the disease. Our findings will significantly advance our understanding of disease pathogenesis in SSc, propel progress in the field, and importantly 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 my program throughout the award period. I will mentor junior physician investigators in the assessment of SSc in patients and the absence of disease in healthy twins, evaluation of Raynaud phenomenon, detection of autoantibodies, obtaining informed consent, banking and use of clinical samples, examination of DNA methylation profiles, measurement of estrogen, and identification of associations with clinical variables. The mentoring goals of this application also include mentoring junior clinician investigators in patient-oriented research, grantsmanship, manuscript writing, responsible conduct of research, entrepreneurship and innovation, and career development. My reputation as an excellent mentor coupled with the collaborative and supportive environment at the Medical University of South Carolina, the resources available at the institution and via the CTSA, and the resources of the Division of Rheumatology P30 CCCR, provide the perfect environment for attracting and training successful clinician investigators. My ultimate goal is to ensure a pipeline of well-trained clinical investigators who will continue the mission of treating patients and identifying the cause and cure for Scleroderma and related diseases.