Biological Roles of Forkhead Box C1 in Pelvic Endometriosis

叉头盒 C1 在盆腔子宫内膜异位症中的生物学作用

• 批准号: 10154109
• 负责人: Gregory Willis Burns
• 金额: $ 6.64万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-02 至 2022-01-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10154109
• 关键词: Affect; Age; Biological; Chronic; Cicatrix; Data; Development; Diagnosis; Diagnostic Procedure; Disease; Disease Progression; Endometrial; Endometrium; Epithelial; Epithelial Cells; Estrogens; Etiology; FOXC1 gene; Female; Fertility; Fibroblasts; Fibrosis; Foundations; GATA6 transcription factor; Gene Expression; Genes; Genetic Transcription; Goals; Health; Human; Impairment; Infertility; Knowledge; Laboratories; Lesion; Mediating; Mesenchymal; MicroRNAs; Modeling; Molecular; Myofibroblast; Non-Malignant; Onset of illness; Papio; Pathogenesis; Pathology; Pathway interactions; Pelvic Pain; Pelvis; Peritoneum; Post-Transcriptional Regulation; Regulation; Regulator Genes; Research; Role; Stromal Cells; System; Testing; Tissues; Training; Transcriptional Regulation; Uterus; Variant; Woman; Work; base; career; chronic pelvic pain; cohort; diagnostic biomarker; differential expression; endometriosis; experience; gain of function; gene repression; improved; insight; noninvasive diagnosis; novel diagnostics; reproductive; reproductive tract; therapeutic target; transcription factor; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Endometriosis is a chronic, estrogen-dependent gynecological disorder affecting 10-15% of reproductive age women which is characterized by the presence of endometrial tissue outside the uterus, predominantly in the pelvic peritoneum, and resulting in pelvic pain and infertility. The long-term goal of this research is discovery of molecular mechanisms governing the pathogenesis of endometriosis, particularly fibrosis, for development of non-invasive diagnostics and fertility-sparing treatments. Lesion etiology is difficult to study in women because of the significant delays of 8-11 years from the onset of disease to diagnosis and variations in disease progression. Over the past 25 years the Fazleabas lab has developed the baboon as an appropriate model to examine the establishment and progression of endometriotic lesions. FOXC1 was identified as a major upstream regulator of differentially expressed genes in lesions compared to matched endometrium from transcriptomic analyses. FOXC1 gain-of-function is associated with tissue remodeling and mechanisms of fibrosis, a hallmark of endometriotic lesions hypothesized to be crucial to the underlying pathogenesis of lesions. Thus, increased expression of FOXC1 may be an important contributor to the development of fibrosis in endometriotic lesions. We hypothesize that increased FOXC1, as a consequence of transcriptional and post-transcriptional regulation, alters the function of epithelial and stromal cells to promote fibrosis in the ectopic endometrium. We will determine the transcriptional and post-transcriptional mechanisms that regulate the increased expression of FOXC1 in endometriotic lesions (Aim 1), and the effects of FOXC1 expression on epithelial to mesenchymal (EMT) and fibroblast to myofibroblast (FMT) transitions, two components that contribute to fibrosis in endometriotic lesions. The proposed studies will provide key insight into the regulation and downstream effects of increased FOXC1 expression to uncover critical mechanisms in the pathogenesis of fibrosis in endometriotic lesions. The technical experience from these studies and career training from my sponsor and co-sponsors will prepare me for a successful independent research career for investigating endometriosis and disorders of the female reproductive tract to improve human health.

项目总结 子宫内膜异位症是一种慢性雌激素依赖型妇科疾病，影响10-15%的生育年龄。 以子宫外子宫内膜组织存在为特征的妇女，主要发生在 盆腔腹膜，并导致盆腔疼痛和不孕。这项研究的长期目标是发现 调控子宫内膜异位症发病的分子机制，尤其是纤维化在子宫内膜异位症发生中的作用 非侵入性诊断和保留生育能力的治疗。女性病变病因学很难研究，因为 从发病到确诊和疾病变异的重大延误时间为8至11年 进步。在过去的25年里，Fazleabas实验室已经开发出适合用于 检查子宫内膜异位病变的建立和进展。FOXC1被确定为主要的上游 病变中差异表达基因的调节与转录后匹配子宫内膜的比较 分析。FOXC1功能获得与组织重塑和纤维化机制有关，这是一个标志 子宫内膜异位症病变被认为对病变的潜在发病机制至关重要。因此，增加了 FOXC1的表达可能是子宫内膜异位症纤维化形成的重要因素。 我们假设FOXC1的增加是转录和转录后调控的结果， 改变异位子宫内膜上皮和间质细胞的功能，促进异位内膜纤维化。我们将决定 Foxc1基因转录及转录后调控机制的研究 子宫内膜异位症病变(目标1)，以及FOXC1表达对上皮至间充质(EMT)和 成纤维细胞到肌成纤维细胞(FMT)的转变，这是导致子宫内膜异位症病变纤维化的两个组成部分。 拟议的研究将为FOXC1增加的调控和下游影响提供关键洞察力 以揭示子宫内膜异位病变纤维化发病机制的关键机制。技术上的 从我的赞助商和共同赞助商那里获得的这些学习和职业培训的经验将为我未来的 成功的独立研究生涯，研究女性子宫内膜异位症和生殖障碍 改善人类健康的途径。