Biological Roles of Forkhead Box C1 in Pelvic Endometriosis

项目摘要 子宫内膜异位症是一种慢性、雌激素依赖性妇科疾病，影响10-15%的育龄妇女 女性，其特征在于子宫外存在子宫内膜组织，主要是在子宫内， 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 控制子宫内膜异位症发病机制的分子机制，特别是纤维化， 非侵入性诊断和生育保留治疗。在女性中很难研究病变的病因， 从发病到诊断的8-11年的重大延误和疾病的变化 进展在过去的25年里，Fazleabas实验室已经将狒狒作为一个合适的模型， 检查增生性病变的建立和进展。FOXC 1被确定为主要的上游 与来自转录组学的匹配子宫内膜相比，病变中差异表达基因的调节因子 分析。FOXC 1功能获得性与组织重塑和纤维化机制相关， 假设对病变的潜在发病机制至关重要。因此， FOXC 1的表达可能是纤维化病变中纤维化发展的重要因素。 我们假设，FOXC 1的增加，作为转录和转录后调节的结果， 改变上皮细胞和基质细胞的功能，促进异位子宫内膜纤维化。我们将确定 转录和转录后机制，调节FOXC 1的表达增加， FOXC 1表达对上皮细胞间质转化（EMT）和细胞增殖的影响。 成纤维细胞到肌成纤维细胞（FMT）的转变，这两种成分有助于纤维化病变中的纤维化。 拟议的研究将为FOXC 1增加的调控和下游效应提供关键的见解。 表达以揭示纤维化病变中纤维化发病机制的关键机制。技术 从这些研究和职业培训的经验，我的赞助商和共同赞助商将准备我 成功的独立研究生涯，调查子宫内膜异位症和女性生殖系统疾病 以改善人类健康。

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.