Defining Gene Expression Programs in Cervical Ripening: Roles for Non-Coding RNAs

定义宫颈成熟中的基因表达程序：非编码 RNA 的作用

• 批准号: 8575168
• 负责人: WILLIAM Lee KRAUS
• 金额: $ 19.88万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8575168
• 关键词: Accounting; Bioinformatics; Biological; Biological Assay; Biological Models; Birth; Cells; Cervical; Cervical Ripening; Cervix Uteri; Child; Clinical; Complex; Country; Data; Detection; Development; Diagnosis; Extracellular Matrix; Fetus; Functional RNA; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Targeting; Genes; Genomics; Goals; Human; Immunoprecipitation; Infection; Inflammation; Kinetics; Knowledge; Luciferases; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular; Mus; Nature; Outcome; Pathway interactions; Physiological Processes; Pregnancy; Premature Birth; Prevention; Process; Prostaglandins; RNA; RNA Sequences; Regulation; Reporter; Risk; Role; Staging; Structure; Technology; Term Birth; Thinking; Tissues; United States; Uterine Contraction; Validation; Woman; base; clinically relevant; crosslink; flexibility; improved; insight; interest; mRNA Expression; mouse model; novel; premature; programs; public health relevance; stillbirth; therapeutic target; tool; transcriptome sequencing

DESCRIPTION (provided by applicant): On an annual basis, 3.3 million babies will die worldwide due to complications in pregnancy that leads to preterm birth (PTB) or stillbirths. While many of the initiating factors remain to be identified, we know that infection accounts for roughly 20-25% of PTBs in the United States and is the primary cause of PTB in underdeveloped countries. 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 may be disrupted during infections. 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 the complete transcriptome, as well as 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 apply cutting-edge genomic, bioinformatic, and computational approaches to the study of infection-mediated gene regulation in a mouse model of infection mediated preterm birth, as well as a complementary model of inflammation in the human cervix to establish proof-of-principle for this approach. Specifically, we will use RNA-seq and Ago HITS-CLIP (high-throughput sequencing of RNAs isolated by crosslinking immunoprecipitation of Argonaute) technologies, in conjunction with cell-based gene-specific assays, to identify, confirm, and explore the gene expression programs that regulate infection mediated cervical ripening in these two complimentary models of cervical infection/inflammation. Validation of gene targets identified in this study will suppor the future potential of these approaches to dissect the molecular pathways that regulate processes critical for successful parturition at term and to understand how regulatory circuits go awry in preterm birth.

描述（由申请人提供）：每年，由于怀孕的并发症导致早产（PTB）或死产，全球330万婴儿将死亡。尽管许多启动因素仍有待确定，但我们知道，在美国，感染占PTB的20-25％，是不发达国家PTB的主要原因。子宫颈重塑 - 将子宫颈从封闭的刚性结构转变为可以打开的过程，以使胎儿通过出生管道通过，这是出生过程中可能被破坏感染过程中的关键组成部分。对驱动术语和感染介导的早产颈重塑的机制的更好理解将提供可用于检测和预防PTB的新见解。在（1）通过mRNA，microRNA和长期非编码RNA（LNCRNA）和（2）通过MIRNA对目标mRNA和NCRNA的作用来调节（1）在（1）（1）在（1）转录水平下调节转录水平的过程。这些机制的整合形成了一个调节电路，允许经过精心调整和仔细协调的基因表达程序。在相关的生物学模型中，鉴定完整的转录组以及microRNA及其靶标mRNA和LNCRNA之间的临床相关相互作用将为介导早产颈椎成熟的生物学机制提供新的见解。当前研究的目的是将尖端的基因组，生物信息学和计算方法应用于感染介导的早产的小鼠模型中感染介导的基因调节的研究，以及人宫颈中炎症的互补模型，以建立这种方法的证明。具体而言，我们将使用RNA-seq和AGO HITS-CLIP（通过对ARGONAUTE的交联免疫沉淀分离的RNA的高通量测序）技术与基于细胞基因的基因特异性测定结合，以识别，确认，确认，确认，确认并探索这些基因表达程序，以调节这些依次介导的卵巢症状模型。在本研究中鉴定出的基因靶标的验证将支持这些方法的未来潜力，以剖析调节过程对成功分娩至关重要的分子途径，并了解监管电路在早产中如何出现。