TGF-BETA Signaling in Myometrial Development and Function

描述(由申请人提供)：子宫肌层在各种女性生殖事件中起着基础作用，并对妊娠结局有重大影响。子宫肌层的结构和功能异常可导致生殖功能障碍，如着床失败、早产和子宫破裂，其中一些是新生儿死亡和发病率的严重原因。尽管长期以来人们认识到子宫肌层功能在妊娠中的重要性，但控制子宫肌层发育和功能的关键信号通路还没有很好的定义。缺乏这方面的知识的部分原因是缺乏一个动物模型，肌层缺陷是由已定义的细胞信号通路中断引起的。这造成了一个重要的障碍，阻碍了对子宫肌层功能障碍的有效治疗干预。 我们这项建议的目标是确定转化生长因子信号转导的作用 在子宫肌层，并确定失调的转化生长因子信号在子宫疾病的发生发展中的作用。我们假设，子宫肌层的发育和功能需要转化生长因子信号，而子宫肌层转化生长因子信号的失调与子宫腺肌病等子宫疾病有关。我们将在两个特定的目标上验证我们的假设：1)确定转化生长因子信号在子宫肌层收缩和妊娠中的作用；2)确定失调的转化生长因子信号在子宫肌层缺陷和子宫腺肌病发展中的作用机制。为了实现这些目标，我们将使用互补的方法，包括条件基因敲除策略和体外测试来测试我们的工作假说。该应用的成功完成将有助于揭示控制子宫肌层结构和功能特性的信号通路，并为理解肌层病理的潜在机制提供一个新的范式。这些数据可能会潜在地指导针对子宫肌层功能障碍和肌层相关疾病的新疗法的设计。

DESCRIPTION (provided by applicant): The myometrium plays a fundamental role in a variety of female reproductive events and has a significant impact on pregnancy outcome. The structural and functional abnormalities of myometrium can lead to reproductive disorders, such as implantation failure, preterm labor, and uterine rupture, some of which are severe causes of neonatal mortality and morbidity. Despite the long-recognized importance of myometrial function in pregnancy, key signaling pathways that control myometrial development and function are not well defined. Lack of this knowledge is partially due to the lack of an animal model with myometrial defects resulting from disruption of defined cell signaling pathways. This creates a significant barrier that prevents an effective therapeutic intervention for myometrial dysfunction. Our objective of this proposal is to define the role of transforming growth factor (TGF) signaling in myometrium, and identify the contribution of dysregulated TGF signaling to the development of uterine diseases. We hypothesize that TGF signaling is required for myometrial development and function, and dysregulated myometrial TGF signaling is linked to uterine diseases such as adenomyosis. We will test our hypothesis in two specific aims: 1) Identify the role of TGF signaling in myometrial contractility and pregnancy; and 2) Define the mechanistic contributions of dysregulated TGF signaling to the development of myometrial defects and uterine adenomyosis. To achieve these aims, we will use complementary approaches including a conditional knockout strategy and in vitro assays to test our working hypotheses. Successful completion of the proposed application will help to uncover the signaling pathways that control the structural and functional properties of the myometrium, and achieve a new paradigm for understanding the mechanisms underlying myometrial pathologies. These data could potentially guide the design of novel therapies for myometrial dysfunction and myometrium-associated diseases.