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: 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
• 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

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

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: American journal of respiratory cell and molecular biology
• 影响因子: 6.4
• 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: Pediatric research
• 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: Science advances
• 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