Novel pathways regulating calcium mediated contractility in the pregnant uterus

在怀孕期间，子宫肌层必须首先保持静止，以允许胎儿生长，然后变成 被激活以有力地收缩并排出成熟的胎儿以独立生活。不完整的理解 调节子宫肌层静止和激活之间的转换的机制， 缺乏预防早产的有效战略，早产是儿童死亡的最大原因 在地球仪上都有不到5岁的儿童。我们最近发现了瞬时受体电位香草酸4 通道（TRPV4）作为子宫肌层收缩性的调节剂。我们发现，钙，最关键的 决定子宫肌层收缩力的蛋白质，可以通过TRPV4进入子宫肌层平滑肌细胞（mSMC）， 与L型钙通道完全不同通过一个协调的、多学科的团队， 将从机制上探讨TRPV4激活促进子宫肌层收缩性的假说 和炎症反应，是治疗早产的一个新的潜在靶点。对TRPV 4的离散关注， 治疗早产的新的治疗靶点是高度创新和重要的， 研究将提供必要的概念验证和机制数据，以允许开发针对 针对TRPV4，这是以前在早产背景下未提及的目标。我们最近发现TRPV4 TRPV4在妊娠期间的表达和定位是动态调节的，TRPV4促进子宫肌层 在两种不同的早产小鼠模型中，阻断TRPV4可抑制妊娠。新 初步数据支持TRPV4也促进子宫肌层炎症的假设， 早产儿因此，靶向TRPV 4可以同时抑制子宫肌层收缩性和子宫内膜收缩性。 炎症，一种可能比靶向单一过程更有效的策略，从而代表了一种 创新和前所未有的战略。在一系列补充目标中，我们将使用 分子、细胞、动物和人类研究的组合。我们首先计划确定 在子宫肌层静止和激活期间使用野生型调节TRPV4表达和活性， 相关基因敲除小鼠，以探索TRPV4结合伴侣，激活，细胞运输和微调控 RNA。第二，使用早产的分子、细胞和小鼠模型，我们将检验以下假设： TRPV4增强子宫肌层炎症。第三个目的是为了证明我们之间的忠诚， 在小鼠模型和人类妊娠中的发现。对人类受试者的研究将提供必要的证据， TRPV4通道在妊娠期间和妊娠期发病时的调节和激活的概念和机制 劳动这些研究的完成将确立TRPV4在调节子宫肌层和平滑肌细胞之间的转换中的作用。 静止和激活，并提供细胞和环境特异性数据，可转化为治疗， 选择性靶向子宫肌层中的TRPV 4。总之，这些数据将建立TRPV 4通道作为一个可行的， 早产是全球婴儿发病率和死亡率的主要原因，是解决这一问题的一个合理和新颖的目标。

During pregnancy, the myometrium must first remain quiescent to permit fetal growth, and then become activated to powerfully contract and expel the mature fetus for independent life. An incomplete understanding of the mechanisms that regulate the switch between myometrial quiescence and activation is highlighted by the absence of effective strategies to prevent preterm delivery, the single greatest cause of mortality in children less than 5 years of age across the globe. We recently identified the transient receptor potential vanilloid 4 channel (TRPV4) as a modulator of myometrial contractility. We showed that calcium, the most critical determinate of myometrial contractility, can enter myometrial smooth muscle cells (mSMC) via TRPV4, a route that is entirely distinct from L-type calcium channels. With a coordinated, multidisciplinary team, this proposal will mechanistically explore the hypothesis that activation of TRPV4 promotes myometrial contractility and inflammation, and is a new potential target to treat preterm labor. The discrete focus upon TRPV4 as a novel therapeutic target for the treatment of preterm labor is highly innovative and significant, as the proposed studies will provide essential proof-of-concept and mechanistic data to permit the development of therapies directed against TRPV4, a target not previously addressed in the context of preterm labor. We recently showed that TRPV4 expression and localization is dynamically regulated during pregnancy, that TRPV4 promotes myometrial contractility, and that blocking TRPV4 prolongs pregnancy in two distinct murine models of preterm labor. New preliminary data support the hypothesis that TRPV4 also promotes myometrial inflammation, a key initiating event in preterm labor. Thus, targeting TRPV4 may simultaneously suppress both myometrial contractility and inflammation, a strategy likely to be more efficacious than targeting a single process, thereby representing an innovative and unprecedented strategy. In a series of complementary aims, we will test our hypothesis using a combination of molecular, cellular, animal, and human studies. We first plan to identify the mechanisms that regulate TRPV4 expression and activity during myometrial quiescence and activation using wild type and relevant knock-out mice to explore TRPV4 binding partners, activation, cell trafficking, and regulation by micro RNAs. Second, using molecular, cellular, and murine models of preterm labor, we will test the hypothesis that TRPV4 enhances myometrial inflammation. The third aim is designed to demonstrate fidelity between our findings in murine models and human pregnancy. Studies in human subjects will provide essential proof of concept and mechanistic insight into TRPV4 channel regulation and activation during pregnancy and at the onset of labor. The completion of these studies will establish a role for TRPV4 in regulating the switch between myometrial quiescence and activation, and provide cell- and context-specific data that can be translated into therapies that selectively target TRPV4 in the myometrium. Together, these data will establish the TRPV4 channel as a viable, rational and novel target to address preterm labor, the major cause of infant morbidity and mortality worldwide.