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Mechanisms by which the myometrial ECM modulates myometrial cell function

子宫肌层 ECM 调节子宫肌细胞功能的机制

基本信息

批准号：
10356896
负责人：
Shanmugasundaram Nallasamy
金额：
$ 24.49万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-11-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10356896
关键词：
Address Area Biological Assay Biology Birth Cell Culture System Cell Proliferation Cell physiology Cells Cervix Uteri Child Clinical Collagen Fiber Competence Connexin 43 Contracts Cues Data Defect Development Down-Regulation Early Diagnosis Elastic Fiber Enzymes Equilibrium Estrogens Extracellular Matrix Extracellular Matrix Proteins Family Family member Fetal Growth Fetus Functional disorder Future Genes Genetic Transcription Goals Growth Health Hormonal In Vitro Infant Mortality Inflammatory Intervention Knowledge Lead Maintenance Mechanics Mediating MicroRNAs Mind Molecular Mus Myometrial Oxytocin Receptor Phase Phenotype Play Pregnancy Premature Birth Prevention Preventive therapy Process Progesterone Protein-Lysine 6-Oxidase Regulation Reporter Research Research Training Risk Factors Rodent Role Signal Transduction Smooth Muscle Myocytes Steroids Structure Survivors Term Birth Testing Tissues Training Uterine Contraction Uterus Vagina base beta Aminopropionitrile career development cell transformation cell type crosslink cyclooxygenase 2 density early pregnancy experience extracellular fetal gene network hormone regulation improved in vivo inhibitor mRNA Expression mechanical signal mechanotransduction mortality risk myometrium pregnant premature pressure prevent programs protein expression public health relevance response steroid hormone therapeutic target uterine contractility

项目摘要

ABSTRACT Preterm birth is a leading cause of infant mortality and can lead to long term health challenges in survivors. Fifteen million children are born prematurely worldwide on an annual basis. Identification of risk factors and development of preventative therapies against preterm birth require improved understanding of the molecular processes that drive parturition at term. Over the course of pregnancy the uterus grows and remodels to accommodate the growing fetus yet remains quiescent until term when the uterus transforms to a contractile state for successful delivery. Fetal, mechanical, hormonal and inflammatory signals collectively regulate the balance between myometrial quiescence and contractility though our understanding of the molecular details remains incomplete. Increased synthesis of extracellular matrix (ECM) proteins noted in rodents in mid- pregnancy support a role for ECM in regulating mechanical signals that may regulate phenotypic changes in the myometrial cell. The focus of this application is to understand the regulatory role of myometrial ECM structure on myometrial cell phenotype and function in pregnancy. With this goal in mind, we will study the role and regulation of lysyl oxidase (LOX), a key enzyme that targets the ECM components collagen and elastic fibers to regulate the stiffness and strength of the ECM. We provide evidence that 1) LOX expression is temporally induced in the mouse myometrium in the synthetic phase (gestation days12 and 15) of myometrial remodeling; 2) inhibition of LOX activity in pregnancy prevents onset of parturition and prevents the induction of contraction associated genes such as connexin 43, oxytocin receptor and prostaglandin endoperoxide synthase 2. We will determine if LOX regulates structural changes in the ECM and functional changes in the myometrium that result in increased strength of the myometrium during the synthetic phase of remodeling. We will also investigate whether LOX-mediated increases in tissue stiffness provides a mechanical signal that is required to transition myometrial cells from quiescence in the synthetic phase to a contractile cell at term. These studies will broaden our understanding of the mechanical signals that regulate the balance between uterine quiescence and contractility and thus lead to identification of therapeutic targets for prevention of premature uterine contractions and preterm birth. In addition these studies will integrate the varied expertise of the applicant and provide the requisite training and career development required for his successful development of a strong independent research program that will address an important and understudied area of uterine biology.

摘要