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