TGF-BETA SIGNALING IN ENDOMETRIAL CELL FUNCTION AND DYSFUNCTION

标题： 转化生长因子-β信号与子宫内膜细胞功能和功能障碍 项目摘要/摘要 越来越多的育龄妇女面临流产和不孕，其中一些是 与子宫内膜功能障碍有关。对子宫内膜的调控机制缺乏了解 发育和功能阻碍了对此类疾病的有效治疗。因此，有一个关键的 需要确定子宫内膜细胞增殖、分化和功能的潜在机制。 由于伦理上的限制，对怀孕期间人类子宫内膜功能的研究仍然具有挑战性 获取组织标本的途径，使小鼠模型特别有价值。转化生长因子β (转化生长因子β)超家族信号调节细胞的基本功能和发育过程 包括子宫在内的生殖器官。转化生长因子β信号在子宫生物学中的体内作用 由于转化生长因子β配体的冗余性和缺乏合适的动物模型，人们对此知之甚少。通过 同时使用功能丧失和功能获得的基因操作转化生长因子β1型受体 小鼠模型，我们发现转化生长因子β信号是生育和雌性生殖道所必需的 发展。在我们令人信服的初步发现的指导下，这份R01提案的总体目标是 破译支持子宫内膜细胞增殖的细胞、分子和表观遗传机制， 分化，和功能。我们的中心假设是子宫内膜细胞的属性和功能 受平衡的转化生长因子β信号系统调节，对子宫发育和怀孕至关重要。我们 我将通过追求以下两个具体目标来检验我们的假设：1)定义转化生长因子β信号如何调节 子宫发育过程中子宫内膜上皮细胞的增殖。2)确定角色和关联 转化生长因子β信号转导在妊娠期子宫内膜间质细胞功能障碍中的作用机制这个 拟议的研究具有创新性，因为它涉及到使用独特的和互补的新型鼠标 解释转化生长因子β信号在子宫内膜细胞中的作用和相关机制的模型 应用子宫上皮和间质细胞培养及共培养系统揭示子宫上皮和间质细胞如何 转化生长因子β信号调节间质-上皮相互作用，这是子宫发育中的一个关键但不明确的事件 和功能，以及TGFBR1在子宫内膜基质中依赖的表观遗传机制的鉴定 细胞。本申请中提出的研究代表着研究连续体的下一步 开发针对子宫内膜功能障碍和妊娠并发症的针对性干预措施。因此， 这一提议的完成有望为理解以下机制提供新的范式 子宫内膜功能障碍，并为未来重点测试子宫内膜功能障碍的研究提供合理的基础 靶向转化生长因子β信号级联在治疗子宫内膜功能障碍中的翻译潜力。

Title: TGF-BETA SIGNALING IN ENDOMETRIAL CELL FUNCTION AND DYSFUNCTION Project Summary/Abstract An increasing number of reproductive-aged women face pregnancy loss and infertility, some of which is associated with endometrial dysfunction. A lack of understanding of mechanisms governing endometrial development and function prevents an effective treatment for such disorders. Therefore, there is a critical need to define the mechanisms underlying endometrial cell proliferation, differentiation, and function. Research on human endometrial function during pregnancy remains challenging due to ethical constrains on the access to tissue specimens, making the mouse model particularly valuable. Transforming growth factor β (TGFβ) superfamily signaling regulates fundamental cellular functions and developmental processes in reproductive organs including the uterus. The in vivo function of TGFβ signaling in uterine biology remains poorly understood due to the redundancy of TGFβ ligands and lack of appropriate animal models. By genetically manipulating TGFβ type 1 receptor (TGFBR1) using both loss-of-function and gain-of-function mouse models, we have discovered that TGFβ signaling is required for fertility and female reproductive tract development. Guided by our compelling preliminary findings, the overall objective in this R01 proposal is to decipher the cellular, molecular, and epigenetic mechanisms underpinning endometrial cell proliferation, differentiation, and function. Our central hypothesis is that endometrial cell properties and function are regulated by a well-balanced TGFβ signaling system essential for uterine development and pregnancy. We will test our hypothesis by pursuing the following two specific aims: 1) Define how TGFβ signaling regulates endometrial epithelial cell proliferation during uterine development. 2) Identify the role and associated mechanism of TGFβ signaling in endometrial stromal cell function and dysfunction during pregnancy. The proposed research is innovative because it involves the use of unique and complementary novel mouse models to decipher the role and associated mechanisms of TGFβ signaling in endometrial cells, the application of uterine epithelial and stromal cell culture and co-culture system to uncover how TGFβ signaling regulates stromal-epithelial interaction, a key but poorly defined event in uterine development and function, and the identification of TGFBR1-dependent epigenetic mechanisms in endometrial stromal cells. Studies proposed in this application represent the next step in a continuum of research toward the development of targeted interventions for endometrial dysfunction and pregnancy complications. Thus, completion of this proposal is expected to provide a new paradigm for understanding the mechanisms of endometrial dysfunction, and provide a rational basis for future research that focuses on testing the translational potential of targeting TGFβ signaling cascade in the treatment of endometrial dysfunction.