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

• 批准号: 9225030
• 负责人: Shanmugasundaram Nallasamy
• 金额: $ 12.56万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9225030
• 关键词: Address; Alpha Cell; 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; 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; experience; extracellular; fetal; hormone regulation; implementation research; improved; in vivo; inhibitor/antagonist; mRNA Expression; mechanotransduction; myometrium; pregnant; premature; pressure; prevent; programs; protein expression; public health relevance; response; steroid hormone; therapeutic target; uterine contractility

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 早产是婴儿死亡的主要原因，并可能导致幸存者的长期健康挑战。 全世界每年有1500万儿童早产。确定风险因素， 预防性治疗早产的发展需要提高对分子生物学的理解， 在足月分娩的过程。在怀孕的过程中，子宫生长并重塑， 适应生长中的胎儿，但仍然保持静止，直到足月时，子宫转变为收缩性子宫。 成功交付的状态。胎儿，机械，激素和炎症信号共同调节 尽管我们对分子细节的了解，子宫肌层静止和收缩之间的平衡 仍然不完整。在啮齿类动物中观察到细胞外基质（ECM）蛋白合成增加， 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， 子宫肌层细胞本申请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结构。带着这个目标，我们将研究 和赖氨酰氧化酶（LOX）的调节，这是一种靶向ECM成分胶原蛋白和弹性蛋白的关键酶， 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 在子宫肌层的合成期（妊娠第12天和第15天）在小鼠子宫肌层中暂时诱导 重塑; 2）在妊娠中抑制LOX活性可防止分娩的发生并防止诱导 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 合成酶2.我们将确定LOX是否调节ECM的结构变化和ECM的功能变化。 在重构的合成阶段期间导致子宫肌层的强度增加。我们 还将研究LOX介导的组织硬度增加是否提供了机械信号， 子宫肌层细胞从合成期的静止状态转变为足月收缩细胞所需的蛋白质。 这些研究将拓宽我们对调节细胞之间平衡的机械信号的理解。 子宫静止和收缩力，从而导致确定治疗靶点， 子宫过早收缩和早产。此外，这些研究将整合各种专业知识， 申请人，并提供必要的培训和职业发展所需的成功， 发展一个强大的独立研究计划，将解决一个重要的和未充分研究的领域 子宫生物学。