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 为准备分娩而进行的宫颈重塑在怀孕早期就开始了，并由一个精确的 颈椎细胞外基质(ECM)的结构和机械功能的时间变化。理解 在维持细胞外基质合成和降解的同时改变妊娠细胞外基质的分子途径 平衡是辨别宫颈功能以及它如何机械地保护胎儿所必需的。更重要的是， 关键是要确定这些宫颈ECM的合成和降解过程何时以及如何受到干扰， 这会损害宫颈的机械功能，并造成早产的风险。我们的团队之前的工作 提供了1)非妊娠和妊娠宫颈快速胶原转换率的证据2)宫颈功能障碍 颈椎细胞外基质导致新型小鼠颈椎生物力学功能紊乱 力学性能随着ECM结构的变化和4)小鼠模型的变化而在不同的阶段演变 颈椎功能障碍是评估颈椎力学的有用工具。在这些发现的基础上，我们的目标是更好地 明确确保细胞外基质动态平衡的胶原降解和弹性纤维弹性形成的分子途径 在生理重建方面。其次，我们的目标是理解推导出的力学参数的复杂性 由多个长度尺度的胶原和弹性纤维组成。总的来说，拟议的研究基于令人信服的 初步的数据，可以扩大我们对颈椎生物学和力学生物学基本机制的理解 扩大肺结核临床干预的可能性。