Identification of Cell-Specific Transcriptional Programs that Drive Cervical Remo

识别驱动宫颈 Remo 的细胞特异性转录程序

• 批准号: 10407489
• 负责人: Mariano Colon-Caraballo
• 金额: $ 7.39万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10407489
• 关键词: 3-Dimensional; 37 weeks gestation; ATAC-seq; Address; Automobile Driving; Birth; Cell Culture System; Cell Nucleus; Cell model; Cell physiology; Cells; Centers for Disease Control and Prevention (U.S.); Cervical; Cervix Uteri; Chromatin; Collagen Fiber; Collagen Fibril; Competence; Complex; Cues; Data; Data Set; Defect; Deposition; Developed Countries; Development; Discipline of obstetrics; Early identification; Elastic Fiber; Enhancers; Estrogens; Etiology; Event; Extracellular Matrix; Extracellular Matrix Proteins; Fetus; Fiber; Foundations; Functional disorder; Future; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Genomics; Goals; Hormonal; Hormones; Human; Incidence; Individual; Infant; K-Series Research Career Programs; Knockout Mice; Knowledge; Lead; Mechanics; Mediating; Mediator of activation protein; Modification; Molecular; Molecular Genetics; Morbidity - disease rate; Mus; Newborn Infant; Outcome; Pathway interactions; Perinatal mortality demographics; Phase; Phenotype; Population; Predictive Factor; Pregnancy; Pregnancy Complications; Pregnancy Maintenance; Premature Birth; Preparation; Prevention; Process; Progesterone; Proteins; Regulator Genes; Regulatory Pathway; Research Personnel; Resolution; Risk; Risk Factors; Role; Signal Transduction; Solid; Stromal Cells; Structure; System; Technology; Testing; Time; Tissues; United States; Validation; Wild Type Mouse; biomarker identification; cell type; cervical remodeling; clinically relevant; conditional knockout; decorin; early pregnancy; gene network; gene regulatory network; in vivo; innovation; mouse model; neonate; novel; perinatal morbidity; post-doctoral training; pregnant; preservation; programs; promoter; reproductive; resilience; single-cell RNA sequencing; steroid hormone; therapeutic target; transcription factor; translational impact

Premature Birth (PTB) is the most common complication during pregnancy leading to a high incidence of perinatal morbidity and mortality rates in developed countries. According to the CDC, in 2018, 1 of every 10 newborns delivered preterm in the United States. An understanding of the molecular processes that determine a successful pregnancy and on time parturition is essential in order to elucidate the diverse mechanisms by which this process can go awry and lead to a premature birth. The transformation of the cervix from a closed rigid structure to one that can open sufficiently for passage of a term infant is one such process. The significance of the proposed studies is the potential to advance understanding of the dynamic molecular events that regulate cervical remodeling at the cellular level. The focus of this application is to utilize innovative single cell genomic technologies that will allow us to define gene regulatory networks that drive cervical remodeling. We will identify regions of active transcription at single cell resolution in the mouse cervix from nonpregnant, time points in pregnancy, and in labor. Utilizing novel computational approaches previously used to study cellular reprogramming events in development, this data will be used to understand how each cell type transitions its phenotype to implement the dynamic process of remodeling and identify the cell specific transcription factors that drive these cell specific molecular changes. Functional validation of the identified transcription factors will be carried out using a human 3D-cervical cell culture system and studies in normal mice and mouse models with targeted deletion of the transcription factors. The proposed studies will provide a solid and broad foundation of understanding of cellular events that drive cervical remodeling which will allow the discovery of risk factors for premature birth that are not yet known and will uncover new pathways to explore for therapeutic targets for prevention of preterm birth. In addition, these studies will provide me the scientific and technical knowledge required for a successful postdoctoral training and importantly, will set the foundation to apply for K awards aiding in my transition to becoming an independent investigator in the reproductive field.

早产（PTB）是妊娠期间最常见的并发症，导致发达国家围产期发病率和死亡率很高。据美国疾病控制和预防中心 (CDC) 称，2018 年，美国每 10 名新生儿中就有 1 人早产。为了阐明这一过程可能出错并导致早产的多种机制，了解决定成功怀孕和按时分娩的分子过程至关重要。子宫颈从封闭的刚性结构转变为可以充分打开以供足月婴儿通过的结构就是这样一个过程。拟议研究的意义在于有可能促进对在细胞水平上调节宫颈重塑的动态分子事件的理解。该应用的重点是利用创新的单细胞基因组技术，使我们能够定义驱动宫颈重塑的基因调控网络。我们将以单细胞分辨率鉴定非妊娠、妊娠和分娩时间点的小鼠子宫颈中的活性转录区域。利用先前用于研究发育中细胞重编程事件的新颖计算方法，这些数据将用于了解每种细胞类型如何转变其表型以实现重构的动态过程，并识别驱动这些细胞特定分子变化的细胞特定转录因子。将使用人类 3D 宫颈细胞培养系统对已识别的转录因子进行功能验证，并在正常小鼠和小鼠模型中进行研究，并有针对性地删除转录因子。拟议的研究将为理解驱动宫颈重塑的细胞事件提供坚实而广泛的基础，这将有助于发现尚不知道的早产危险因素，并将揭示新的途径来探索预防早产的治疗靶点。此外，这些研究将为我提供成功博士后培训所需的科学和技术知识，更重要的是，将为申请 K 奖奠定基础，帮助我过渡到成为生殖领域的独立研究者。