Vascular remodeling in the ovary

卵巢血管重塑

• 批准号: 10724873
• 负责人: JOHN S DAVIS
• 金额: $ 15.35万
• 依托单位: UNIVERSITY OF NEBRASKA 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: 2023-08-04 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10724873
• 关键词: 3-Dimensional; Adult; Affect; Angiogenesis Inhibitors; Angiogenic Factor; Atlases; Blood Vessels; CDH5 gene; Cattle; Cell Death; Cells; Conditioned Culture Media; Cytokine Gene; Cytokine Receptors; Data; Development; Endometrium; Endothelial Cells; Endothelium; Excision; Fertility; First Pregnancy Trimester; Foundations; Freezing; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene set enrichment analysis; Genes; Genetic Transcription; Gland; Goals; Granulosa-Lutein Cells; Human; In Vitro; Infertility; Inflammation Mediators; Inflammatory; Intramuscular Injections; Knowledge; Livestock; Luteal Cells; Luteal Phase; Luteolysis; Mediating; Mediator; Modeling; Nuclear RNA; Organ; Organoids; Ovarian; Ovary; Ovulation; Pathway interactions; Peptide Initiation Factors; Physiology; Pregnancy; Pregnancy Maintenance; Process; Production; Progesterone; Prostaglandins; Reporting; Research; Saline; Secretory Cell; Signal Transduction; Structure; System; Termination of pregnancy; Testing; Tissues; Up-Regulation; Uterus; Vascular Endothelial Cell; Vascular remodeling; Vascularization; angiogenesis; cell type; corpus luteum; cytokine; differential expression; gene induction; gene repression; genetic signature; gonad function; granulosa cell; in vitro Model; in vivo; insight; lipid mediator; nonhuman primate; novel; receptor; release factor; reproductive; response; single nucleus RNA-sequencing; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Corpus luteum removal during the first trimester of pregnancy leads to pregnancy termination. With rising infertility rates and ~25% of pregnancies ending in the first trimester, research in luteal physiology is increasingly relevant. Disruption of luteal function is mediated by inflammatory cytokines and lipid mediators. The key lipid mediator prostaglandin F2α (PGF2α) is produced within the gland in humans and non-human primates and by the non-pregnant endometrium in domestic farm animals. The corpus luteum is one of the most vascularized organs in the adult body. Development of the luteal vasculature following ovulation is vital for the production of progesterone. The luteal vasculature is unique because it is possibly the only case of full angiogenesis and angioregression in the adult. When the corpus luteum regresses at the end of a non-fertile reproductive cycle, microvascular endothelial cells are the first cells to die. However, these cells do not express receptors for the luteolytic signal, PGF2α. Only the steroidogenic large luteal cells (LLC), which derive from the granulosa cells of the ovulated follicle, possess this receptor in the corpus luteum. Therefore, the endothelial cell death response during the early stages of regression is likely initiated by factors released by large luteal cells in response to PGF2α. Our overarching hypothesis is that the disruption of endothelial cell networks during luteal regression are due to factors produced by large luteal cells in response to PGF2α. The goals of this study are to: (1) identify cell-specific temporal changes in gene transcription during induced luteal regression in vivo, and (2) conduct mechanistic studies to determine mediators of luteal angioregression utilizing a novel 3D organoid culture system. We will use single nuclear RNA sequencing (snRNA-seq) to determine the cell-type specific temporal patterns of gene expression during luteal regression. Hypothesis: Large steroidogenic luteal cells respond to PGF2α by rapidly increasing production of inflammatory mediators and anti-angiogenic factors, followed by induction of genes in endothelial cells that contribute to vascular disruption and cell death. We recently developed novel 3D luteal organoid model to allow us to determine which large luteal cell secretory product(s) affect the regression of luteal endothelial structures. Hypothesis: inflammatory mediators produced by LLC will disrupt endothelial networks and alter cell fate. The state-of-the-art approach using snRNA-seq profiling will provide the first unbiased transcriptomic atlas of the cell type specific gene expression in the corpus luteum. The studies will provide novel insight into the temporal changes in gene expression in specific luteal cell types during the process of luteal regression. Successful completion of the proposed research will fill a gap in knowledge about the pathways crucial for maintaining gonadal function and identify novel mechanisms by which the lipid mediator PGF2α disrupts gonadal function. Insight into luteal angioregression will provide the foundations for identifying mechanisms to maintain vasculature structures in the ovary and other reproductive tissues.

项目摘要 妊娠前期妊娠中期的叶黄素清除导致妊娠终止。带着复活 不育率和约25％的妊娠孕期结束时，黄体生理学的研究越来越多 相关的。黄体功能的破坏是由炎症细胞因子和脂质介质介导的。钥匙脂质 介体ProstaglandinF2α（PGF2α）在人类和非人类隐私中产生，并通过 非妊娠子宫内膜在家畜动物中。 Luteum是最血管的之一 成人身体中的器官。排卵后黄体脉管系统的发展对于生产至关重要 孕酮。黄体脉管系统是独一无二的，因为这可能是全血管生成和 成年人的血管造成。当Luteum在非毛皮复制循环结束时回归时， 微血管内皮细胞是第一个死亡的细胞。但是，这些单元不表达接收器 黄体信号，PGF2α。只有类固醇大的大黄内细胞（LLC），该细胞源自 排卵的叶子，潜在的叶黄素中该受体。因此，内皮细胞死亡反应 在回归的早期阶段，可能是由大型黄体细胞释放的因素引发的 PGF2α。我们的总体假设是黄体回归期间内皮细胞网络的破坏 是由于大型黄体细胞对PGF2α产生的因素。这项研究的目标是：（1）确定 细胞特异性临时变化在体内诱导的黄体回归过程中的基因转录和（2）传导 使用新型的3D器官培养 系统。我们将使用单个核RNA测序（SNRNA-SEQ）来确定细胞类型的临时性 黄体回归过程中基因表达的模式。假设：大型类固醇生成的黄体细胞对 PGF2α通过迅速增加炎症介质和抗血管生成因子的产生，然后是 在内皮细胞中诱导基因，导致血管破坏和细胞死亡。我们最近开发了 新型的3D黄体器官模型，使我们能够确定哪种大型黄体细胞分泌产物影响 黄体内皮结构的回归。假设：LLC生产的炎症介质会破坏 内皮网络并改变细胞命运。使用SNRNA-SEQ分析的最新方法将提供 叶黄素中细胞类型特异性基因表达的第一个无偏转录图。研究会 在此过程中，在特定的黄体细胞类型中提供了基因表达暂时变化的新见解 黄体回归。成功完成拟议的研究将填补有关知识的空白 途径对于维持性腺功能至关重要，并确定脂质介体的新型机制 PGF2α破坏了性腺功能。对黄体血管造影的洞察力将为识别基础提供基础 维持卵巢和其他生殖组织中脉管结构的机制。