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.

摘要 子宫颈为分娩做准备的重塑始于妊娠早期， 宫颈细胞外基质（ECM）结构和机械功能的定时变化。理解 在妊娠期间改变ECM的分子途径，同时维持ECM的合成和降解， 平衡对于辨别宫颈功能以及它如何机械地保护胎儿是必要的。更重要的是， 关键是确定这些宫颈ECM合成和降解过程何时以及如何受到干扰， 这损害了子宫颈的机械功能并产生早产的风险。我们的团队在工作之前 提供了证据1）非妊娠和妊娠子宫颈胶原蛋白周转率快速2）功能障碍 在新的小鼠模型中，颈部细胞外基质导致颈部生物力学功能破坏 机械性能在不同的阶段与ECM结构的变化相一致，4） 颈椎功能障碍是评价颈椎力学有用工具。基于这些发现，我们的目标是更好地 确定胶原蛋白降解和弹性纤维弹性生成的分子途径，确保ECM稳态 在生理重塑方面。其次，我们的目标是了解力学参数的复杂性， 从胶原蛋白和弹性纤维在多个长度尺度。总的来说，拟议的研究，基于令人信服的 初步数据，可以扩大我们对宫颈生物学和机械生物学基本机制的理解 并扩大了临床干预PTB的可能性。