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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

基本信息

批准号：
9759670
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
项目类别：
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/9759670
关键词：
Address Affect Area Attention Award Biopsy Cells Cervical Cervix Uteri Characteristics Collagen Complex Contracts Defect Discipline of obstetrics Etiology Exhibits Exposure to Extracellular Matrix Fetus Functional disorder Gene Expression Gene Expression Profile Genetic Transcription Gestational Age Goals Health Healthcare Human Inflammation Inflammatory Institutional Review Boards Investigation 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 mechanotransduction molecular phenotype novel novel therapeutics pregnant premature pressure prevent programs response skills transcriptome

项目摘要

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.

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