Identification of Cell-Specific Transcriptional Programs that Drive Cervical Remo

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高。根据疾病预防控制中心的数据，2018年，美国每10个新生儿中就有1个早产。了解决定成功怀孕和准时分娩的分子过程对于阐明这一过程可能出错并导致早产的各种机制至关重要。宫颈从一个封闭的刚性结构转变为一个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。提出的研究的意义在于有可能在细胞水平上促进对调节颈椎重塑的动态分子事件的理解。这项应用的重点是利用创新的单细胞基因组技术，这将使我们能够定义驱动颈椎重塑的基因调控网络。我们将在小鼠子宫颈中从未怀孕、怀孕和分娩的时间点识别单细胞分辨率的活性转录区域。利用以前用于研究发育过程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塑的动态过程，并确定驱动这些细胞特异性分子变化的细胞特异性转录因子。鉴定的转录因子的功能验证将使用人类3d宫颈细胞培养系统进行，并在正常小鼠和靶向删除转录因子的小鼠模型中进行研究。这些研究将为理解驱动颈椎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清楚的早产风险因素，并将为探索预防早产的治疗靶点提供新的途径。此外，这些研究将为我提供成功的博士后培训所需的科学和技术知识，重要的是，将为我申请K奖奠定基础，帮助我过渡到生殖领域的独立研究者。

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.