Functional and Molecular Characterization of Epithelial Subtypes in Cervical Remodeling and Preterm Birth

宫颈重塑和早产中上皮亚型的功能和分子特征

• 批准号: 10681015
• 负责人: MALA S. MAHENDROO
• 金额: $ 63.05万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-24 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681015
• 关键词: Automobile Driving; Basal Cell; Biological Markers; Cell Differentiation process; Cell Proliferation; Cell physiology; Cells; Cervical; Cervix Uteri; Clinical; Columnar Epithelium; Computer Analysis; Data; Data Set; Defect; Disease; Ensure; Epithelial Cells; Epithelium; Estrogens; Exposure to; Eye; Fertility; Functional disorder; Gastrointestinal tract structure; Gel; Gene Expression; Genetic Transcription; Goals; Goblet Cells; Health; Homeostasis; Hormones; Immunologic Surveillance; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory Response; Knowledge; Late pregnancy; Lipopolysaccharides; Liquid substance; Lung; Measures; Mediating; Microbe; Modeling; Molecular; Monitor; Mucous Membrane; Mucous body substance; Mus; Natural Immunity; OLFM4 gene; Organoids; Outcome; Phase; Phenotype; Pilot Projects; Play; Population; Pregnancy; Pregnancy Maintenance; Premature Birth; Prevention; Process; Production; Progesterone; Proliferating; Prostate; Regulation; Risk; Risk Factors; Role; Secretory Cell; Signal Transduction; Sorting; Specificity; Squamous Epithelium; Steroids; System; Testing; Therapeutic; Time; Woman; Work; biomarker identification; cell type; cervical remodeling; cervicovaginal; experimental study; gene regulatory network; immune function; improved; in vivo; infection risk; insight; pathogen; prevent; progenitor; programs; response; risk prediction; single cell analysis; single-cell RNA sequencing; stem cell biomarkers; stem cells; steroid hormone; transcription factor; transcriptomics; transdifferentiation; vaginal fluid

Abstract Preterm birth due to an ascending infection accounts for 25-40% of spontaneous preterm births. Disruptions in the cervical epithelia that perturb its barrier and immune function is a risk factor for an ascending infection. Using single cell transcriptomic and spatial approaches, epithelia subpopulations were identified in cervices from nonpregnant mice and mice at gestation days 6, 12, 15, 18 and in labor. Unique to pregnancy was the expansion of two populations of secretory goblet cells which produce a distinct mucus network and immune surveillance factors. In the current proposal, we aim to identify the lineage of these secretory cells which express markers of both squamous and columnar epithelia, and to define the progesterone and estrogen dependent gene regulatory networks that regulate proliferation and differentiation of the two goblet subtypes. Using single cell datasets from mice with epithelial barrier defects or mice with exposure to lipopolysaccharide to induce inflammation, we will define perturbations in epithelial subtype functions that contribute to ascending infection risk. Finally, the expression of olfactomedin 4, one immune surveillance factor upregulated in the goblet cells in pregnancy, will be measured in cervico-vaginal fluid from women in each trimester of a term or preterm pregnancy to determine its utility to monitor cervical epithelial cell health and risk of spontaneous preterm births.

摘要 上行性感染引起的早产占自发性早产的25-40%。中断 扰乱其屏障和免疫功能的宫颈上皮是上行感染的危险因素。使用 单细胞转录组学和空间方法，在宫颈中鉴定了上皮细胞亚群， 非妊娠小鼠和妊娠第6、12、15、18天和分娩中的小鼠。怀孕的独特之处在于 分泌杯状细胞的两个群体，产生不同的粘液网络和免疫监视 因素在目前的建议中，我们的目标是确定这些分泌细胞的谱系，这些分泌细胞表达的标志物， 鳞状上皮和柱状上皮，并确定孕激素和雌激素依赖的基因调控 调节两种杯状亚型增殖和分化的网络。使用单像元数据集 上皮屏障缺陷的小鼠或暴露于脂多糖以诱导炎症的小鼠，我们将 定义上皮亚型功能的扰动，导致感染风险上升。最后 嗅觉调节素4是一种在妊娠期杯状细胞中上调的免疫监视因子， 在足月或早产的每个三个月的妇女的宫颈阴道液中进行测量，以确定 其用于监测宫颈上皮细胞健康和自发性早产风险的实用性。