The Role of Hormonal Dysregulation in Systemic Sclerosis

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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.