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 为分娩做准备的子宫颈重塑在怀孕早期就开始了，并且是由精确的组织精心策划的。 宫颈细胞外基质（ECM）的结构和机械功能的定时变化。理解 改变妊娠期 ECM 同时维持合成和降解的分子途径 平衡对于辨别宫颈功能及其如何机械地保护胎儿是必要的。更重要的是， 确定这些宫颈 ECM 合成和降解过程何时以及如何受到干扰至关重要， 这会损害宫颈机械功能并造成早产风险。我们组前期工作 提供证据 1) 非怀孕和怀孕子宫颈中胶原蛋白的快速周转率 2) 功能失调 宫颈细胞外基质在新型小鼠模型中导致宫颈生物力学功能破坏 3) 宫颈 机械性能在不同阶段随着 ECM 结构的变化而演变，4) 小鼠模型 颈椎功能障碍是评估颈椎力学的有用工具。基于这些发现，我们的目标是更好地 定义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 在生理重塑中。其次，我们的目的是了解导出的机械参数的复杂性 来自多种长度尺度的胶原蛋白和弹性纤维。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力学生物学基本机制的理解 并扩大PTB临床干预的可能性。