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重要作用，并对妊娠结局产生重大影响。子宫肌层的结构和功能异常可导致生殖障碍，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的严重原因。尽管子宫肌层功能在妊娠中的重要性早已被认识到，但控制子宫肌层发育和功能的关键信号通路尚未得到很好的定义。缺乏这方面的知识，部分是由于缺乏一个动物模型与子宫肌层缺陷所造成的破坏确定的细胞信号传导途径。这产生了一个显著的障碍，阻止了对子宫肌层功能障碍的有效治疗干预。 我们的目标是确定转化生长因子（TGF）信号转导的作用， 在子宫肌层，并确定的贡献失调的TGF信号传导的子宫疾病的发展。我们假设TGF信号传导是子宫肌层发育和功能所需的，而子宫肌层TGF信号传导失调与子宫腺肌病等子宫疾病有关。我们将在两个具体目标中检验我们的假设：1）确定TGF信号传导在子宫肌层收缩和妊娠中的作用; 2）确定TGF信号传导失调对子宫肌层缺陷和子宫腺肌病发展的机制贡献。为了实现这些目标，我们将使用互补的方法，包括条件性敲除策略和体外试验来测试我们的工作假设。成功完成所提出的应用将有助于揭示控制子宫肌层结构和功能特性的信号通路，并为理解子宫肌层病理机制提供新的范例。这些数据有可能指导子宫肌层功能障碍和子宫肌层相关疾病的新疗法的设计。 公共卫生相关性：我们的建议与NICHD的使命相关，因为TGF信号通路在调节雌性生殖中至关重要。子宫肌层在各种女性生殖事件中起着重要作用，并对妊娠结局有重要影响。因此，揭示TGF信号通路在子宫肌层发育和功能中的作用将可能导致发现新的子宫肌层功能障碍和子宫疾病的诊断和治疗策略。

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. PUBLIC HEALTH RELEVANCE: Our proposal is relevant to the mission of NICHD because TGF signaling pathway is critical in regulation of female reproduction. The myometrium plays a fundamental role in a variety of female reproductive events and has a significant impact on pregnancy outcome. Therefore, uncovering the role of TGF signaling pathway in myometrial development and function will potentially lead to the discovery of novel diagnostic and therapeutic strategies for myometrial dysfunction and uterine diseases.