The Role of Hormonal Dysregulation in Systemic Sclerosis

激素失调在系统性硬化症中的作用

• 批准号: 10370661
• 负责人: DeAnna Baker Frost
• 金额: $ 18.64万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-17 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10370661
• 关键词: Advisory Committees; Affect; African American; African American population; Age; Aromatase Inhibitors; Autoantibodies; Autoimmune Diseases; Basic Science; Bioinformatics; Biological Markers; Biology; Caucasians; Cessation of life; Characteristics; Clinical; Clinical Research; Cost of Illness; Cutaneous; Data Analyses; Dehydroepiandrosterone Sulfate; Dermal; Diagnosis; Diffuse; Diffuse Scleroderma; Direct Costs; Disease; Disease Outcome; Estradiol; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Extracellular Matrix; FDA approved; Facilities and Administrative Costs; Female; Fibroblasts; Fibronectins; Fibrosis; Fostering; Foundations; Fulvestrant; Gender; Gene Expression; Gene Expression Profile; General Population; Genetic Transcription; Genomics; Goals; Gonadal Steroid Hormones; Hormonal; Human; In Vitro; Knock-out; Knockout Mice; Measures; Mediator of activation protein; Mentors; Modeling; Morbidity - disease rate; Mus; Outcome; Pathogenesis; Patients; Pharmaceutical Preparations; Postmenopause; Production; Profibrotic signal; Prognosis; Protein Isoforms; Receptor Signaling; Research; Research Institute; Research Support; Resources; Rheumatology; Role; Serum; Severities; Severity of illness; Signal Transduction; Skin; Skin Tissue; South Carolina; Systemic Scleroderma; Testing; Testosterone; Time; Tissue-Specific Gene Expression; Training; Translational Research; Woman; career; career development; clinical center; cohort; dehydroepiandrosterone; disability; ethnic diversity; experience; in vivo; innovation; mRNA sequencing; male; mortality; mouse model; negative affect; new therapeutic target; non-genomic; novel; personalized medicine; potential biomarker; prevent; sex; skin fibrosis; supportive environment; targeted treatment; time interval; transcriptomics

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.

尽管系统性硬化症 (SSc) 患者的残疾、发病率和死亡率有所增加，但目前尚无 FDA 批准的 SSc 药物可预防或逆转纤维化。我们的长期目标是了解 E2 如何 影响 SSc 的纤维化，这为使用抑制 E2 产生的药物和 用于 SSc 治疗的信号传导（分别为芳香酶抑制剂和氟维司群）。本次活动的总体目标 建议确定 E2 诱导的纤维化所需的雌激素受体 (ER)，即转录组学 人类皮肤中 E2 和 ER 信号传导引起的变化，以及全身 E2 水平和 疾病结果。核心假设是荷尔蒙失调会随着时间的推移促进真皮纤维化 通过 ER 进行依赖性信号传播，导致促纤维化基因转录增加和 SSc 恶化 临床结果。该项目的基本原理是通过结合以下因素来了解 E2 如何导致纤维化： 雌二醇的细胞、转录组和全身效应。我们将用以下具体内容来检验我们的假设 目标：(1) 确定 ER 在 E2 诱导的真皮纤维化中的作用； (2) 确定新的转录组 E2诱导的离体真皮纤维化概况； (3) 确定荷尔蒙失调之间的关联 和 SSc 的临床结果。在第一个目标中，我们将使用 3 个模型来研究 ER 如何影响纤维化：人类 体外和小鼠原代真皮成纤维细胞，体内 ERα 缺失和 GPER1 KO 小鼠，以及人类皮肤组织 体内。第二个目标，我们将在不同时间点用E2刺激人体皮肤以评估差异基因 使用 mRNA seq 进行表达并确定哪些 ER 负责这些特定的转录组 变更。在第三个目标中，我们将比较性激素 E2、硫酸脱氢表雄酮和 患有有限性 SSc 和弥漫性 SSc 的非裔美国人和白种人患者以及健康人的睾酮水平 控制和估计激素水平、自身抗体状态和疾病临床指标之间的关联 严重程度。该项目具有创新性，因为了解 ER（ERα 亚型和 GPER1）在纤维化中的作用 性激素和 SSc 之间临床关联的发现提高了全身性使用的前景 激素水平作为 SSc 疾病特征、严重程度和预后的生物标志物。拟议的研究 意义重大，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 是利用基础科学和临床来了解SSc相关纤维化和雌激素之间的关系 研究，希望开发个性化的医学目标。为了实现这个目标，我将获得 受体信号生物学、生物信息数据解释和临床研究方面的培训。 MUSC 包含 资源，例如临床研究核心中心和 CTSA 赞助的南卡罗来纳州临床与研究中心 转化研究所提供必要的研究支持和职业发展。我的导师 共同导师、咨询委员会和风湿病科都营造了一个支持性的环境， 允许成功完成该提案并继续迈向独立。