The Role of Hormonal Dysregulation in Systemic Sclerosis

尽管系统性硬化症(SSC)患者的残疾、发病率和死亡率增加，但目前 FDA批准的治疗SSc的药物可以预防或逆转纤维化。我们的长期目标是了解E2是如何 影响SSC的纤维化，这为使用抑制E2产生和 SSC治疗的信号转导(分别为芳香酶抑制剂和弗维斯特)。这个项目的总体目标是 建议确定雌激素诱导的纤维化所需的雌激素受体(ER)，转录 人类皮肤中E2和ER信号的改变，以及系统E2水平和ER信号之间的关系 疾病后果。中心假说是，随着时间的推移，激素失调会促进皮肤纤维化-- 通过内质网依赖的信号传递(S)，导致促纤维化基因转录增加和更糟糕的SSc 临床结果。这个项目的基本原理是通过结合雌激素是如何导致纤维化的 雌二醇的细胞、转录和全身效应。我们将使用以下具体内容来验证我们的假设 目的：(1)确定雌激素受体在雌激素诱导的皮肤纤维化中的作用；(2)确定新的转录因子 雌激素诱导的体外皮肤纤维化的概况；以及(3)确定激素失调之间的关系 和SSC的临床结果。在第一个目标中，我们将使用3个模型来检查ER如何影响纤维化：人类 和体外培养的小鼠原代真皮成纤维细胞，体内ERα缺失和GPER1KO小鼠，以及人皮肤组织 活着。在第二个目标中，我们将在不同的时间点用雌二醇刺激人类皮肤，以评估差异基因 使用mRNA序列进行表达，并确定哪些ER负责这些特定的转录 改装。在第三个目标中，我们将比较性激素E2、硫酸脱氢表雄酮和 非裔美国人和高加索人局限性SSc和弥漫性SSc患者以及健康人的睾酮 控制和评估激素水平、自身抗体状态和疾病临床指标之间的关系 严肃性。该项目具有创新性，因为了解了ER(ERα亚型和GPER1)在纤维化中的作用 发现性激素和SSc之间的临床联系增加了使用系统性红斑狼疮的前景 激素水平可作为SSc疾病特征、严重程度和预后的生物标志物。拟议的研究 具有重要意义，因为它为使用雌激素调节剂治疗SSC提供了基础。我的长期职业目标 从基础科学和临床角度了解SSc相关纤维化与雌激素的关系 研究，希望开发个性化的药物靶点。为了实现这个目标，我将获得 受体信号生物学、生物信息学数据解释和临床研究方面的培训。MUSC包含 资源，如核心临床研究中心和CTSA赞助的南卡罗来纳州临床与 翻译研究所，提供必要的研究支持和职业发展。我的导师 联合导师、咨询委员会和风湿科都营造了一个支持性的环境， 使这项提案得以顺利完成，并继续向独立迈进。

Although patients with systemic sclerosis (SSc) have increased disability, morbidity, and mortality, no current FDA-approved medications for SSc prevent or reverse fibrosis. Our long-term goal is to understand how E2 influences fibrosis in SSc, which provides the rationale for using medications that inhibit E2 production and signaling (aromatase inhibitors and fulvestrant, respectively) for SSc treatment. The overall objectives of this proposal are to identify the estrogen receptors (ERs) needed for E2-induced fibrosis, the transcriptomic alterations caused by E2 and ER signaling in human skin, and any associations between systemic E2 levels and disease outcomes. The central hypothesis is that hormonal dysregulation promotes dermal fibrosis through time- dependent signal propagation via ER(s), leading to increased pro-fibrotic gene transcription and worse SSc clinical outcomes. The rationale for this project is to understand how E2 leads to fibrosis by incorporating the cellular, transcriptomic and systemic effects of estradiol. We will test our hypothesis with the following specific aims: (1) Identify the contribution of ERs in E2-induced dermal fibrosis; (2) Determine the novel transcriptomic profile of E2-induced dermal fibrosis ex vivo; and (3) Determine associations between hormonal dysregulation and clinical outcomes in SSc. In the first aim, we will use 3 models to examine how ERs affect fibrosis: human and mouse primary dermal fibroblasts in vitro, ERα-null and GPER1 KO mice in vivo, and human skin tissue ex vivo. In the second aim, we will stimulate human skin with E2 at various time points to assess differential gene expression using mRNA seq and determine which ERs are responsible for these specific transcriptomic alterations. In the third aim, we will compare levels of the sex hormones E2, dehydroepiandrosterone sulfate and testosterone in African American and Caucasian patients with limited SSc and diffuse SSc as well as in healthy controls and estimate associations among hormonal level, autoantibody status, and clinical measures of disease severity. The project is innovative because understanding the role of ERs (ERα isoforms and GPER1) in fibrosis and discovering clinical associations between sex hormones and SSc raise the prospect of using systemic hormonal levels as a biomarker for SSc disease characteristics, severity and prognosis. The proposed research is significant because it provides the basis for using estrogen modulators to treat SSc. My long-term career goal is to understand the relationship between SSc-related fibrosis and estrogen using basic science and clinical research, with the hope of developing personalized medicine targets. To accomplish this goal, I will obtain training in receptor signaling biology, bioinformatic data interpretation and clinical research. MUSC contains resources such as the Core Center for Clinical Research and the CTSA-sponsored South Carolina Clinical & Translational Research Institute which provide necessary research support and career development. My mentor and co-mentor, advisory committee and the Division of Rheumatology all foster a supportive environment, allowing for successful completion of this proposal and continued progression toward independence.