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: 9164454
• 负责人: Joy-Sarah Vink
• 金额: $ 13万
• 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/9164454
• 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; Gestational Age; Goals; Health; Healthcare; Human; Inflammation; Inflammatory; Institutional Review Boards; Knowledge; Matrix Metalloproteinases; Mechanics; Mediating; Mentors; Molecular; Muscle Contraction; 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; meetings; 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.

抽象的： 自发性早产 (sPTB) 仍然是一个重大的产科难题，给美国带来了巨大的损失。 卫生保健。 sPTB的病因各不相同，但最终的共同途径涉及宫颈过早重塑 (PCR)、缩短和扩张。尽管这个健康问题很重要，但正常和正常的病理生理学 人类的 PCR 尚不清楚。例如，宫颈平滑肌细胞（CSMC）在 宫颈重塑仍然未知。五年来，在我杰出的指导下 导师，我从事宫颈重塑研究并帮助建立了 Collaborative Cervix 哥伦比亚大学研究小组（CCRG）。 CCRG 的目标是解决以下复杂问题： PCR 采用真正的多学科方法。我的初步工作表明，内部操作系统中的 CSMC 是 圆周方向（类似于“括约肌”），来自内口的宫颈组织响应收缩 催产素。我认为 CSMC 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，胎儿生长的压力会拉伸到子宫颈。我推测华润上华 拉伸引起收缩（以维持括约肌张力）和/或 ECM 重塑。此外，我假设 患有 PCR 的女性表现出异常的颈椎拉伸反应、收缩力和/或 ECM 重塑。在 目标 1，我将从有（研究组）和没有的女性中拉伸妊娠宫颈组织活检和 CSMC PCR（对照，CTL）确定 1) 拉伸是否会引起宫颈收缩力，2) 宫颈和 CSMC 是否来自 患有 PCR 的女性表现出异常的收缩力，并且 3) 潜在的收缩机制可以解释 收缩性缺陷。在目标 2 中，我将调查进行 PCR 1) 的女性的宫颈组织和 CSMC 是否表现出 异常拉伸反应导致 MMP 激活、胶原蛋白更新/ECM 重塑增加 与 CTL 相比，2) 炎症是否进一步增强这种拉伸诱导的 MMP 激活/ECM 重塑。在目标 3 中，我将评估转录组中是否存在拉伸诱导的分子表型变化 PCR 与 CTL 女性的 CSMC 水平，特别关注收缩性和 ECM 重塑 途径。为了实现这一目标，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 中提取。如果患有 PCR 的女性有 1) CSMC 无法收缩并维持“括约肌样”张力以响应拉伸和/或 2) 表现出异常 ECM 重塑对拉伸的反应导致子宫颈机械强度变弱，这可能解释了为什么子宫颈 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研究技能，这样我就可以实现我的最终目标 成为一名成功且独立的临床科学家，其重点是预防 PCR 和 PTB。