Evaluating the role of human cervical smooth muscle cells in normal and premature cervical remodeling

评估人宫颈平滑肌细胞在正常和过早宫颈重塑中的作用

• 批准号: 9313747
• 负责人: Joy-Sarah Vink
• 金额: $ 16.77万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9313747
• 关键词: Address; Affect; Area; Attention; Award; Biopsy; Cells; Cervical; Cervix Uteri; Characteristics; Collagen; Complex; Contracts; Defect; Discipline of obstetrics; Etiology; Exhibits; Extracellular Matrix; Fetus; Functional disorder; Gene Expression; Gene Expression Profile; Genetic Transcription; Gestational Age; Goals; Health; Healthcare; Human; Inflammation; Inflammatory; Investigation; Knowledge; Matrix Metalloproteinases; Mechanics; Mediating; Mentors; Molecular; Oxytocin; Pathway interactions; Pregnancy; Pregnant Women; Premature Birth; Premature Infant; Process; Proteins; Protocols documentation; Recording of previous events; Regulatory Pathway; Research; Risk; Role; Sampling; Scientist; Smooth Muscle Myocytes; Sphincter; Stretching; Termination of pregnancy; Testing; Time; Tissues; Training; Translating; Universities; Uterus; Validation; Woman; Work; clinical care; cost; crosslink; delivery complications; disability; genome-wide; interdisciplinary approach; knowledge base; mechanotransduction; molecular phenotype; novel; novel therapeutics; pregnant; premature; pressure; prevent; programs; response; skills; transcriptome

ABSTRACT: Spontaneous preterm birth (sPTB) remains a significant obstetric dilemma with enormous costs to U.S. healthcare. The etiology of sPTB varies, but the final common pathway involves premature cervical remodeling (PCR), shortening and dilation. Despite the importance of this health issue, the pathophysiology of normal and PCR in humans is not well understood. For instance, the role of cervical smooth muscle cells (CSMCs) in cervical remodeling remains unknown. Over the last five years, under the guidance of my outstanding mentors, I have engaged in studies of cervical remodeling and helped to establish the Collaborative Cervix Research Group (CCRG) at Columbia University. The goal of the CCRG is to tackle the complex problem of PCR from a truly multidisciplinary approach. My initial work established that CSMCs at the internal os are circumferentially oriented (similar to a “sphincter”) and cervical tissue from the internal os contracts in response to oxytocin. I propose that CSMCs may have two key functions: contraction and/or ECM remodeling. As pregnancy grows, the pressure from the growing fetus applies stretch to cervix. I hypothesize that CSMC stretch induces contraction (to maintain sphincter tone) and/or ECM remodeling. Further, I hypothesize that women with PCR exhibit abnormal cervical stretch responses, contractile force and/or ECM remodeling. In Aim 1, I will stretch pregnant cervical tissue biopsies and CSMCs from women with (study group) and without PCR (controls, CTL) to establish 1) if stretch induces cervical contractility, 2) if cervices and CSMCs from women with PCR exhibit aberrant contractility and 3) potential contractile mechanisms which may explain the contractility defect. In Aim 2, I will investigate if cervical tissue and CSMCs from women with PCR 1) exhibit abnormal stretch responses resulting in increased MMP activation, collagen turnover/ECM remodeling compared to CTLs and 2) if inflammation further enhances this stretch-induced MMP activation/ECM remodeling. In Aim 3, I will evaluate if stretch-induced molecular phenotypic changes exist at the transcriptome level in CSMC from women with PCR vs CTL with particular attention to contractility and ECM remodeling pathways. Toward this goal, I have been collecting tissue from pregnant women with a history of PCR and from gestational age-matched CTLs using IRB approved protocols. If women with PCR have 1) CSMCs that cannot contract and maintain “sphincter-like” tone in response to stretch and/or 2) exhibit abnormal ECM remodeling responses to stretch resulting in a mechanically weaker cervix, this may explain why the cervix ultimately fails leading to sPTB. With the guidance of my mentors and CCRG team, this award will allow me to expand my experimental knowledge base and investigational skills so I may achieve my ultimate goal of becoming a successful and independent clinician scientist whose focus is to prevent PCR and PTB.

摘要： 自发性早产（sPTB）仍然是一个重大的产科困境，给美国带来了巨大的成本。 健康护理sPTB的病因各不相同，但最终共同途径涉及过早的宫颈重塑 (PCR)缩短和扩张。尽管这一健康问题的重要性，正常和 人类的PCR还不太清楚。例如，子宫颈平滑肌细胞（CSMCs）在 宫颈重塑仍不清楚。在过去的五年里，在我杰出的指导下， 导师们，我从事了宫颈重塑的研究并帮助建立了协作宫颈 研究小组（CCRG）在哥伦比亚大学。CCRG的目标是解决以下复杂问题： PCR从真正的多学科方法。我最初的工作确定了内部操作系统的CSMC是 环周定向的（类似于“括约肌”）和来自内口的宫颈组织响应收缩 催产素。我建议，CSMCs可能有两个关键功能：收缩和/或ECM重塑。作为 随着怀孕的增长，来自胎儿的压力会对子宫颈产生拉伸作用。我假设CSMC 牵拉诱导收缩（以维持括约肌张力）和/或ECM重塑。此外，我假设， 患有PCR的妇女表现出异常的宫颈拉伸反应、收缩力和/或ECM重塑。在 目标1，我将对患有（研究组）和不患有（研究组）的女性进行妊娠宫颈组织活检和CSMC PCR（对照，CTL）以确定1）拉伸是否会诱导宫颈收缩，2）宫颈和CSMC是否来自 患有PCR的女性表现出异常的收缩力和3）潜在的收缩机制，这可能解释了 收缩性缺陷在目标2中，我将研究来自PCR女性的宫颈组织和CSMCs是否表现出 异常牵张反应导致MMP活化增加，胶原蛋白周转/ECM重塑 和2）如果炎症进一步增强这种牵张诱导的MMP活化/ECM 重塑在目标3中，我将评估在转录组中是否存在牵张诱导的分子表型变化 来自PCR与CTL女性的CSMC水平，特别关注收缩性和ECM重塑 途径。为了实现这个目标，我一直在收集有PCR病史的孕妇的组织， 使用IRB批准的方案从胎龄匹配的CTL中获得。如果患有PCR的女性有1）CSMC， 不能响应拉伸而收缩和维持“括约肌样”张力和/或2）表现出异常ECM 对拉伸的重塑反应导致宫颈机械性较弱，这可能解释了为什么宫颈 最终失败导致sPTB。在我的导师和CCRG团队的指导下，这个奖项将使我能够 扩大我的实验知识基础和调查技能，使我可以实现我的最终目标， 成为一个成功的和独立的临床科学家，其重点是防止PCR和PTB。