Mechanisms of infection-mediated cervical ripening

感染介导的宫颈成熟机制

基本信息

批准号：
9252296
负责人：
MALA S. MAHENDROO
金额：
$ 38.6万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
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：
2016-04-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9252296
关键词：
Affect Architecture Automobile Driving Bioinformatics Biological Biological Assay Biological Markers Biological Models Biological Process Biomechanics Birth CRISPR/Cas technology Cell Culture System Cell Line Cells Cervical Cervical Ripening Cervix Uteri Child Clinical Code Computer Analysis Correlative Study Country Data Data Set Detection Development Ensure Epithelial Cells Etiology Extracellular Matrix Fetus Future Gene Expression Genes Genetic Transcription Genomic approach Goals Health Human Immune Infant Mortality Infection Length Literature Macrophage Activation Mechanics Mediating Messenger RNA MicroRNAs Mifepristone Molecular Mus Mutation Ontology Outcome Pathway interactions Permeability Physiology Play Postpartum Period Predisposition Pregnancy Premature Birth Preparation Prevention Prevention therapy Process Prostaglandins RNA Recording of previous events Regulation Reporter Risk Role Seeds Stromal Cells Structure Survivors System Term Birth Testing Tissues United States Untranslated RNA Uterine Contraction Validation Woman accurate diagnosis base clinically relevant differential expression experience imaging approach improved insight knock-down mRNA Expression macrophage monocyte mouse model novel premature programs public health relevance repaired reproductive tract therapeutic target tissue repair tool tool development transcriptome transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Infection accounts for 25-40% preterm births in the United States and is the primary cause of preterm birth in underdeveloped countries. Evidence that preparation for parturition begins early in pregnancy and that mechanisms of preterm birth are distinct from term and dependent on etiology, emphasize the need to define pathway specific regulatory mechanisms. Cervical remodeling - the process by which the cervix is transformed from a closed rigid structure to one that can open to allow passage of a term fetus through the birth canal - is a key component of the birth process that precedes onset of uterine contractions in term and preterm birth. A better understanding of mechanisms that drive term and infection-mediated preterm cervical remodeling will provide new insights that can be used for the detection and prevention of PTB. The processes that govern cervical remodeling in term or preterm birth are regulated at (1) the transcriptional level by the expression of mRNAs, microRNAs, and long non-coding RNAs (lncRNAs) and (2) the post-transcriptional level by the actions of miRNAs on target mRNAs and ncRNAs. The integration of these mechanisms forms a regulatory circuit that allows finely tuned and carefully coordinated gene expression programs. The identification of clinically relevant interactions between microRNAs and their target mRNAs and lncRNAs in relevant biological models, will provide new insights into the biological mechanisms that mediate premature cervical ripening. The goal of the current study is to computationally interrogate recently generated cervical polyA+ RNA-Seq and microRNA microarray datasets from term and infection-mediated preterm mouse models to identify regulated microRNAs and their predicted mRNAs and lncRNA targets. A 3D-human cervical stromal cell culture system and cell based gene specific assays will be established in order to validate ~ 10 microRNA:target RNA interactions that will be selected using specific criteria such. Finally the impact of an infection-mediated preterm birth on postpartum cervical repair and cervical function/risk of prematurity in a second pregnancy will be investigated comprehensively using tissue biomechanics, physiology as well as cutting edge imaging and genomic approaches. Collectively these studies will dissect the molecular pathways that regulate processes critical for successful parturition at term and define the regulatory circuits that go awry in infection-mediated preterm birth.

描述（由申请人提供）：在美国，感染占早产的比例为 25-40%，并且是欠发达国家早产的主要原因。有证据表明，早产的准备工作在怀孕早期就开始了，而且早产的机制与早产不同。术语并取决于病因，强调需要定义途径特定的调节机制 - 子宫颈从封闭的刚性结构转变为可以打开以允许阴道通过的过程。足月胎儿通过产道 - 是足月和早产子宫收缩之前的分娩过程的关键组成部分，更好地了解驱动足月和感染介导的早产宫颈重塑的机制将提供可使用的新见解。用于检测和预防 PTB 控制足月或早产子宫颈重塑的过程在 (1) 转录水平上受到 mRNA、microRNA 和长非编码 RNA (lncRNA) 的表达的调节。 (2) miRNA 对靶 mRNA 和 ncRNA 的作用的转录后水平，这些机制的整合形成了一个调节回路，可以对 microRNA 及其之间的临床相关相互作用进行微调和仔细协调。相关生物模型中的目标 mRNA 和 lncRNA 将为介导宫颈早熟的生物学机制提供新的见解。当前研究的目标是通过计算询问最近生成的宫颈 PolyA+ RNA-Seq 和 microRNA。来自足月和感染介导的早产小鼠模型的微阵列数据集，用于识别受调节的 microRNA 及其预测的 mRNA 和 lncRNA 靶标。将建立 3D 人宫颈基质细胞培养系统和基于细胞的基因特异性测定，以验证约 10 个 microRNA：靶标。将使用特定标准选择 RNA 相互作用，最后将使用组织全面研究感染介导的早产对产后宫颈修复和宫颈功能/第二次妊娠早产风险的影响。生物力学、生理学以及尖端成像和基因组方法将共同剖析调节足月成功分娩的关键过程的分子途径，并确定感染介导的早产中出错的调节回路。