The Role of Hormonal Dysregulation in Systemic Sclerosis

激素失调在系统性硬化症中的作用

基本信息

批准号：
10685579
负责人：
DeAnna Baker Frost
金额：
$ 18.66万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
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/10685579
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 Estradiol Receptors 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 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 Transforming Growth Factor Beta 2 Transforming Growth Factor beta Translational Research Woman career career development clinical center cohort 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

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 Estradiol Receptors 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 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 Transforming Growth Factor Beta 2 Transforming Growth Factor beta Translational Research Woman career career development clinical center cohort 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

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项目摘要

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.

尽管全身性硬化症患者（SSC）的残疾，发病率和死亡率增加，但没有电流 FDA批准的用于SSC预防或反向纤维化的药物。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产生和的药物提供了理由 SSC处理的信号传导（分别为芳香酶抑制剂和全vestort）。总体目标建议是识别E2诱导的纤维化所需的雌激素受体（ER）由E2和ER信号引起的改变，以及全身E2水平与疾病结果。中心假设是，在时间 - 通过ER的依赖信号传播，导致促纤维化基因转录增加，SSC较差临床结果。该项目的基本原理是了解E2如何通过合并来导致纤维化雌二醇的细胞，转录组和全身效应。我们将使用以下特定的特定来检验我们的假设目的：（1）确定ER在E2诱导的皮肤纤维化中的贡献；（2）确定新颖的转录组 E2诱导的真皮纤维化的特征；（3）确定激素失调之间的关联和SSC的临床结果。在第一个目标中，我们将使用3种模型来检查ERS如何影响纤维化：人类小鼠原发性皮肤成纤维细胞体外，ERα-NULL和GPER1 KO小鼠体内以及人皮肤组织EX 体内。在第二个目标中，我们将在各个时间点用E2刺激人皮，以评估差异基因使用mRNA SEQ表达并确定哪些ER负责这些特定的转录组改变。在第三个目标中，我们将比较性激素E2的水平，脱氢epiandrostrosterone硫酸盐和 SSC和弥漫性SSC以及健康的非裔美国人和高加索患者的睾丸激素以及健康荷尔蒙水平，自身抗体状态和疾病临床指标之间的控制和估计关联严重程度。该项目具有创新性，因为了解ERS（ERα同工型和GPER1）在纤维化中的作用并发现性激素与SSC之间的临床关联提高了使用全身性的前景激素水平是SSC疾病特征，严重程度和预后的生物标志物。拟议的研究之所以重要，是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要使用基础科学和临床了解与SSC相关的纤维化与雌激素之间的关系研究，希望开发个性化医学靶标。为了实现这一目标，我将获得接受受体信号生物学，生物信息学数据解释和临床研究的培训。 MUSC包含诸如临床研究核心中心和CTSA赞助的南卡罗来纳州临床和翻译研究所提供必要的研究支持和职业发展。我的精神以及咨询委员会和风湿病学委员允许成功完成该提案，并持续向独立发展。