Novel pathways regulating calcium mediated contractility in the pregnant uterus

调节妊娠子宫钙介导的收缩性的新途径

基本信息

批准号：
10373975
负责人：
Cristina Maria Alvira
金额：
$ 49.14万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10373975
关键词：
5 year old Address Adipocytes Agonist Animals Arrestins Binding Calcium Cations Cell Adhesion Molecules Cell membrane Cell model Cells Cervix Uteri Child Contracts Cytosol Data Development Event Fetal Growth Fetus Human Infant Mortality Inflammation Inflammatory Investigation Ion Channel Knockout Mice Knowledge L-Type Calcium Channels Labor Onset Life Lipopolysaccharides Mediating MicroRNAs Modeling Molecular Molecular Target Myometrial NF-kappa B Neonatal Mortality Pathway interactions Peptide Hydrolases Permeability Pharmacology Post-Translational Protein Processing Pregnancy Pregnant Uterus Premature Birth Premature Labor Process Prostaglandins Proteins Regulation Role Route Series Smooth Muscle Myocytes Stimulus Stretching Swelling Temperature Testing Tissues Translating Uterine Contraction Vanilloid Woman beta-arrestin chemokine cytokine design experimental study extracellular human subject infant morbidity infant morbidity/mortality innovation insight molecular modeling mortality mouse model multidisciplinary myometrium neonatal morbidity new therapeutic target novel pregnant prevent protein expression protein protein interaction receptor targeted treatment therapy development trafficking transcription factor

项目摘要

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.

在怀孕期间，子宫肌层必须首先保持静止状态以允许胎儿生长，然后变成激活以强力收缩和排出成熟胎儿的独立生活。不完全的理解调节子宫肌层静止和激活之间转换的机制由缺乏有效的策略来预防早产，早产是儿童死亡的最大原因全球范围内年龄不超过 5 岁。我们最近发现了瞬时受体电位香草酸 4 通道（TRPV4）作为子宫肌层收缩力的调节剂。我们证明钙是最关键的决定子宫肌层收缩力，可以通过 TRPV4（一种途径）进入子宫肌层平滑肌细胞 (mSMC) 这与 L 型钙通道完全不同。通过协调一致的多学科团队，该提案将机械地探索 TRPV4 激活促进子宫肌层收缩力的假设和炎症，是治疗早产的新的潜在目标。对 TRPV4 的离散关注为治疗早产的新治疗靶点具有高度创新性和重要意义，因为所提出的研究将提供必要的概念验证和机制数据，以允许开发针对性的疗法反对TRPV4，这是一个以前在早产背景下未解决的目标。我们最近表明 TRPV4 TRPV4 的表达和定位在妊娠期间动态调节，促进子宫肌层在两种不同的早产小鼠模型中，阻断 TRPV4 可以延长妊娠时间。新的初步数据支持这样的假设：TRPV4 也会促进子宫肌层炎症，这是一个关键的起始事件在早产中。因此，靶向TRPV4可能同时抑制子宫肌层收缩力和炎症，这种策略可能比针对单一过程更有效，因此代表了一种创新且前所未有的战略。在一系列互补的目标中，我们将使用分子、细胞、动物和人类研究的结合。我们首先计划确定机制使用野生型和相关敲除小鼠探索 TRPV4 结合伴侣、激活、细胞运输和微调节 RNA。其次，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。第三个目标旨在展示我们之间的忠诚度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怀孕期间和怀孕初期 TRPV4 通道调节和激活的概念和机制见解劳动。这些研究的完成将确定 TRPV4 在调节子宫肌层之间的转换中的作用。静止和激活，并提供细胞和上下文特定的数据，这些数据可以转化为治疗方法选择性地靶向子宫肌层中的 TRPV4。这些数据共同将使 TRPV4 通道成为一个可行的、解决早产问题的合理而新颖的目标，早产是全世界婴儿发病和死亡的主要原因。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Vitamin D: Feel It in More Than Just Your Bones!

维生素 D：不仅仅是在骨骼中感受到它！

DOI：
发表时间：
2020
期刊：
影响因子：
6.4
作者：
Cornfield; David N
通讯作者：
David N

Rare to "Ubiquitinous": Alveolar Capillary Dysplasia, FOXF1, and a Sly Approach to Angiogenesis.

罕见到“普遍”：肺泡毛细血管发育不良、FOXF1 和血管生成的巧妙方法。

DOI：
发表时间：
2023-04-15
期刊：
影响因子：
24.7
作者：
Cornfield, David N;Nogee, Lawrence M
通讯作者：
Nogee, Lawrence M

Hypoxia-Inducible Factor-1α in SM22α-Expressing Cells Modulates Alveolarization.

SM22α 表达细胞中的缺氧诱导因子 1α 调节肺泡化。

DOI：
发表时间：
2023-10
期刊：
影响因子：
6.4
作者：
Barnes, Elizabeth A;Knutsen, Carsten;Kindt, Alida;Che, Xibing;Ying, Lihua;Adams, Eloa;Gonzalez, Erika;Oak, Prajakta;Hilgendorff, Anne;Alvira, Cristina M;Cornfield, David N
通讯作者：
Cornfield, David N

Integrative analysis of noncoding mutations identifies the druggable genome in preterm birth.

非编码突变的综合分析确定了早产中的可药物基因组。

DOI：
发表时间：
2024-01-19
期刊：
影响因子：
13.6
作者：
Wang, Cheng;Wang, Yuejun Jessie;Ying, Lihua;Wong, Ronald J;Quaintance, Cecele C;Hong, Xiumei;Neff, Norma;Wang, Xiaobin;Biggio, Joseph R;Mesiano, Sam;Quake, Stephen R;Alvira, Cristina M;Cornfield, David N;Stevenson, David K;Shaw, Gary M;Li
通讯作者：
Li

Diverse homeostatic and immunomodulatory roles of immune cells in the developing mouse lung at single cell resolution.

单细胞分辨率下发育中的小鼠肺中免疫细胞的多种稳态和免疫调节作用。

DOI：
发表时间：
2020-06-02
期刊：
影响因子：
7.7
作者：
Domingo;Zanini, Fabio;Che, Xibing;Liu, Min;Jones, Robert C;Swift, Michael A;Quake, Stephen R;Cornfield, David N;Alvira, Cristina M
通讯作者：
Alvira, Cristina M