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：
10115771
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/10115771
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 hormone regulation improved in vivo inhibitor/antagonist mRNA Expression mechanotransduction mortality risk myometrium organizational structure 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.

抽象的早产是婴儿死亡的主要原因，并可能给幸存者带来长期的健康挑战。全球每年有 1500 万儿童早产。识别风险因素和开发针对早产的预防性疗法需要加深对分子机制的了解推动足月分娩的过程。在怀孕过程中，子宫会生长并重塑容纳成长中的胎儿，但保持静止状态，直到足月子宫转变为收缩状态状态为成功交付。胎儿、机械、激素和炎症信号共同调节通过我们对分子细节的理解，实现子宫肌层静止和收缩性之间的平衡仍然不完整。啮齿类动物中细胞外基质（ECM）蛋白的合成增加妊娠支持 ECM 在调节机械信号中的作用，机械信号可能调节表型变化子宫肌细胞。该应用的重点是了解子宫肌层 ECM 的调节作用妊娠期子宫肌层细胞表型和功能的结构。带着这个目标，我们将研究这个角色赖氨酰氧化酶 (LOX) 的调节，这是一种针对 ECM 成分胶原蛋白和弹性的关键酶纤维来调节 ECM 的刚度和强度。我们提供的证据表明 1) LOX 表达是在子宫肌层的合成阶段（妊娠第 12 天和第 15 天）在小鼠子宫肌层中暂时诱导改造； 2) 妊娠期抑制LOX活性可防止临产并阻止引产收缩相关基因，如连接蛋白 43、催产素受体和前列腺素内过氧化物合酶 2。我们将确定 LOX 是否调节 ECM 的结构变化和导致子宫肌层在重塑的合成阶段强度增加。我们还将研究 LOX 介导的组织硬度增加是否提供机械信号将子宫肌细胞从合成期的静止状态转变为足月时的收缩细胞所需的。这些研究将拓宽我们对调节之间平衡的机械信号的理解。子宫静止和收缩力，从而确定预防子宫收缩的治疗靶点子宫过早收缩和早产。此外，这些研究将整合不同专业知识申请人并提供其成功所需的必要培训和职业发展制定一个强大的独立研究计划，解决一个重要且未充分研究的领域子宫生物学。