Role of chromatin remodeling and cell signaling in endometriosis etiology

项目摘要 子宫内膜异位症影响10%-15%的育龄妇女，是疼痛和不孕的主要原因。 子宫内膜异位症通常与炎症和雌激素依赖的非肿瘤性扩散有关。 将子宫内膜组织转移到腹膜腔。虽然目前关于子宫内膜异位症病因的理论支持 生理功能障碍在子宫内膜中的作用(即逆行月经)、遗传学和分子生物学 人们对这种疾病的病因机制知之甚少。最新的外显子组测序 子宫内膜异位症病变发现了与染色质重塑和细胞信号转导有关的蛋白质突变。我们 假设染色质重塑和细胞信号通路的突变激活转录 细胞传播和侵袭所需的程序，导致雌激素依赖性的传播 子宫内膜组织。在目标1中，我们将利用遗传和全基因组测序方法来确定 染色质重塑调节正常子宫内膜上皮细胞特性和功能的机制 动态平衡。在目标2中，我们将使用一种新开发的子宫内膜异位症小鼠模型，它模仿自然的 子宫内膜异位症组织的扩散以解决激活蛋白-1(AP-1)信号转录因子的作用 入侵的复杂性。这一提议将提供对促进最初的 子宫内膜异位症的形成和扩散。

Project Summary Endometriosis affects 10-15% of women of reproductive age and is a leading cause of pain and infertility. Endometriosis is commonly associated with inflammation and the estrogen dependent, non-neoplastic spread of endometrial tissue to the peritoneal cavity. While current theories on the causes of endometriosis support a role for physiological dysfunction in the endometrium (i.e. retrograde menstruation), the genetic and molecular mechanisms underlying the etiology of the disease are poorly understood. Recent exome sequencing of endometriotic lesions identified mutations in proteins involved in chromatin remodeling and cell signaling. We hypothesize that mutations in chromatin remodeling and cell signaling pathways activate transcriptional programs required for cellular dissemination and invasion, leading to the estrogen-dependent spread of endometrial tissue. In Aim 1, we will utilize genetic and genome-wide sequencing approaches to determine the mechanism by which chromatin remodeling regulates normal endometrial epithelial cell identity and homeostasis. In Aim 2, we will use a newly developed mouse model of endometriosis that mimics the natural spread of endometriotic tissue to address the role of the Activator Protein-1 (AP-1) signaling transcription factor complex in invasion. This proposal will provide insight into the molecular mechanisms that promote the initial establishment and spread of endometriosis.