Molecular and Mechanical Investigations to Define Collagen and Elastic Fiber Homeostasis in Cervical Remodeling During a Term and Preterm Pregnancy

定义足月和早产期间宫颈重塑中胶原蛋白和弹性纤维稳态的分子和力学研究

• 批准号: 10752526
• 负责人: MALA S. MAHENDROO
• 金额: $ 69.93万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752526
• 关键词: Acceleration; Animal Model; Automobile Driving; Biology; Biomechanics; Birth; Birth Rate; Cell Culture System; Cervical; Cervical Ripening; Cervix Incompetence; Cervix Uteri; Clinical; Collagen; Collagen Fiber; Collagen Fibril; Data; Defect; Degradation Pathway; Diagnosis; Elastic Fiber; Elastin Fiber; Ensure; Equilibrium; Estrogen Therapy; Estrogens; Event; Extracellular Matrix; FBLN5 gene; FBN1; Fetus; Fibrillar Collagen; Functional disorder; Genetic; Genetic Transcription; Homeostasis; Human; Inflammation; Inflammatory; Intervention; Investigation; Knockout Mice; Knowledge; Length; Leucine; Maintenance; Measures; Mechanics; Mediating; Metabolism; Metalloproteases; Modality; Modeling; Molecular; Multiscale Mechanics; Mus; Mutation; Pathway interactions; Peptide Hydrolases; Phase; Physiological; Post-Translational Protein Processing; Postpartum Period; Pregnancy; Premature Birth; Premature Infant; Prevention; Prevention therapy; Process; Progesterone; Property; Proteoglycan; Proteomics; Regulation; Risk; Risk Assessment; Role; Stromal Cells; Structural defect; Structure; Structure-Activity Relationship; Testing; Tissues; Woman; Work; biglycan; biomarker identification; cervical remodeling; clinically relevant; crosslink; decorin; density; disability; extracellular; insight; mechanical properties; mortality risk; mouse model; novel; posttranscriptional; pregnant; premature; programs; repaired; resilience; spatiotemporal; steroid hormone; tool

Abstract The remodeling of the cervix to prepare for birth begins early in pregnancy and is orchestrated by a precisely timed change in the structure and mechanical function of the cervical extracellular matrix (ECM). Understanding the molecular pathways that alter the ECM in pregnancy while maintaining a synthesis and degradation equilibrium is necessary to discern cervical function and how it mechanically protects the fetus. More importantly, it is critical to determine when and how these cervical ECM synthesis and degradation processes are perturbed, which compromise cervical mechanical function and creates a risk for preterm birth. Our groups prior work provides evidence 1) of rapid collagen turnover rates in both nonpregnant and pregnant cervix 2) dysfunctional cervical extracellular matrix leads to disrupted cervical biomechanical function in novel mouse models 3) cervical mechanical properties evolve in distinct stages in concert with shifts in ECM structure and 4) mouse models of cervical dysfunction are a useful tool to evaluate cervical mechanics. Building on these findings, we aim to better define molecular pathways of collagen degradation and elastic fiber elastogenesis that ensure ECM homeostasis in physiologic remodeling. Secondly, we aim to understand the complexity of mechanical parameters derived from collagen and elastic fibers at multiple length scales. Collectively, the proposed studies, based on compelling preliminary data, can expand our understanding of basic mechanisms in cervical biology and mechanobiology and expand the possibilities for clinical intervention in PTB.

抽象的 子宫颈准备生育的重塑始于怀孕初期，并精确地精心策划 宫颈外基质（ECM）的结构和机械功能的定时变化。理解 在维持合成和降解的同时改变ECM的分子途径 平衡对于识别宫颈功能以及它如何机械保护胎儿是必要的。更重要的是， 确定这些宫颈ECM合成和降解过程的何时以及如何干扰至关重要， 这损害了宫颈机械功能，并产生了早产的风险。我们的团体事先工作 提供证据1）非怀孕和怀孕子宫颈的快速胶原周转率2）功能失调 颈细胞外基质导致新小鼠模型中的宫颈生物力学功能破坏3）宫颈 机械性能在ECM结构的变化和4）小鼠模型的一致阶段发展 宫颈功能障碍是评估宫颈力学的有用工具。在这些发现的基础上，我们的目标是更好 定义胶原蛋白降解和弹性纤维弹性发生的分子途径，以确保ECM稳态 在生理重塑中。其次，我们旨在了解得出的机械参数的复杂性 从多个长度尺度上的胶原蛋白和弹性纤维。共同基于引人注目的拟议研究 初步数据可以扩展我们对宫颈生物学和机械生物学基本机制的理解 并扩大PTB临床干预的可能性。