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:
- 金额:$ 49.14万
- 依托单位:
- 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:
- 关键词:5 year oldAddressAdipocytesAgonistAnimalsArrestinsBindingCalciumCationsCell Adhesion MoleculesCell membraneCell modelCellsCervix UteriChildContractsCytosolDataDevelopmentEventFetal GrowthFetusHumanInfant MortalityInflammationInflammatoryInvestigationIon ChannelKnockout MiceKnowledgeL-Type Calcium ChannelsLabor OnsetLifeLipopolysaccharidesMediatingMicroRNAsModelingMolecularMolecular TargetMyometrialNF-kappa BNeonatal MortalityPathway interactionsPeptide HydrolasesPermeabilityPharmacologyPost-Translational Protein ProcessingPregnancyPregnant UterusPremature BirthPremature LaborProcessProstaglandinsProteinsRegulationRoleRouteSeriesSmooth Muscle MyocytesStimulusStretchingSwellingTemperatureTestingTissuesTranslatingUterine ContractionVanilloidWomanbeta-arrestinchemokinecytokinedesignexperimental studyextracellularhuman subjectinfant morbidityinfant morbidity/mortalityinnovationinsightmolecular modelingmortalitymouse modelmultidisciplinarymyometriumneonatal morbiditynew therapeutic targetnovelpregnantpreventprotein expressionprotein protein interactionreceptortargeted treatmenttherapy developmenttraffickingtranscription 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,以允许胎儿生长,然后变成
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:10.1165/rcmb.2020-0072ed
- 发表时间:2020
- 期刊:
- 影响因子:6.4
- 作者:Cornfield,DavidN
- 通讯作者:Cornfield,DavidN
Mentor-Mentee interactions: a 2-way street. The APS-SPR virtual chat series.
- DOI:10.1038/s41390-021-01431-8
- 发表时间:2022-10
- 期刊:
- 影响因子:3.6
- 作者:Cornfield DN;October TW;Libby AM;Abman SH
- 通讯作者:Abman SH
Integrative analysis of noncoding mutations identifies the druggable genome in preterm birth.
- DOI:10.1126/sciadv.adk1057
- 发表时间:2024-01-19
- 期刊:
- 影响因子:13.6
- 作者:Wang C;Wang YJ;Ying L;Wong RJ;Quaintance CC;Hong X;Neff N;Wang X;Biggio JR;Mesiano S;Quake SR;Alvira CM;Cornfield DN;Stevenson DK;Shaw GM;Li J
- 通讯作者:Li J
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Cristina Maria Alvira其他文献
Cristina Maria Alvira的其他文献
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{{ truncateString('Cristina Maria Alvira', 18)}}的其他基金
Pericytes and postnatal alveolarization: Role of hypoxia inducible factors
周细胞和出生后肺泡化:缺氧诱导因素的作用
- 批准号:
10467727 - 财政年份:2022
- 资助金额:
$ 49.14万 - 项目类别:
Pericytes and postnatal alveolarization: Role of hypoxia inducible factors
周细胞和出生后肺泡化:缺氧诱导因素的作用
- 批准号:
10615235 - 财政年份:2022
- 资助金额:
$ 49.14万 - 项目类别:
Developmental Heterogeneity of Pulmonary Endothelial Phenotype at Single Cell Resolution
单细胞分辨率肺内皮表型的发育异质性
- 批准号:
10678976 - 财政年份:2021
- 资助金额:
$ 49.14万 - 项目类别:
Developmental Heterogeneity of Pulmonary Endothelial Phenotype at Single Cell Resolution
单细胞分辨率肺内皮表型的发育异质性
- 批准号:
10211048 - 财政年份:2021
- 资助金额:
$ 49.14万 - 项目类别:
Diverse Homeostatic Roles for Distinct Macrophages in the Developing Lung Vasculature
不同巨噬细胞在发育中的肺血管系统中的多种稳态作用
- 批准号:
10583456 - 财政年份:2021
- 资助金额:
$ 49.14万 - 项目类别:
Diverse Homeostatic Roles for Distinct Macrophages in the Developing Lung Vasculature
不同巨噬细胞在发育中的肺血管系统中的多种稳态作用
- 批准号:
10362528 - 财政年份:2021
- 资助金额:
$ 49.14万 - 项目类别:
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
- 批准号:
9893885 - 财政年份:2018
- 资助金额:
$ 49.14万 - 项目类别:
Novel Molecular Mechanisms Regulating Postnatal Pulmonary Angiogenesis
调节产后肺血管生成的新分子机制
- 批准号:
8686276 - 财政年份:2014
- 资助金额:
$ 49.14万 - 项目类别:
Novel Molecular Mechanisms Regulating Postnatal Pulmonary Angiogenesis
调节产后肺血管生成的新分子机制
- 批准号:
9059764 - 财政年份:2014
- 资助金额:
$ 49.14万 - 项目类别:
Novel Molecular Mechanisms Regulating Postnatal Pulmonary Angiogenesis
调节产后肺血管生成的新分子机制
- 批准号:
9265926 - 财政年份:2014
- 资助金额:
$ 49.14万 - 项目类别:
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