Control of ovarian vascular remodeling by CCAAT/enhancer binding proteins alpha and beta

CCAAT/增强子结合蛋白α和β控制卵巢血管重塑

• 批准号: 10684822
• 负责人: YI REN
• 金额: $ 34.44万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-16 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684822
• 关键词: 3-Dimensional; Abbreviations; Ablation; Address; Affect; Age; Animals; Blood Vessels; Blood flow; CCAAT-Enhancer-Binding Protein-alpha; Cells; Cellular Assay; Chromatin; Data; Data Set; Defect; Epigenetic Process; Event; Failure; Female infertility; Fertility; Foundations; Gene Expression; Genes; Goals; Image; Impairment; Infertility; Knowledge; Link; Luteinizing Hormone; Maps; Mediating; Mediator; Metabolism; Methodology; Methods; Molecular; Morphogenesis; Mus; Mutant Strains Mice; Obesity; Outcome; Ovarian; Ovary; Ovulation; Permeability; Physiological Processes; Play; Process; Regulation; Research; Risk; Role; Rupture; Series; Signal Pathway; Signal Transduction; Site; Technology; Testing; Time; Transcriptional Regulation; Transgenic Mice; Transposase; United States; Vascular Endothelial Cell; Vascular Permeabilities; Vascular remodeling; Woman; cell type; constriction; data integration; design; diet-induced obesity; effective therapy; epigenetic regulation; experimental study; female fertility; genomic data; granulosa cell; improved; in vivo; infertility treatment; innovation; insight; intravital imaging; mouse model; multiphoton microscopy; mutant; next generation sequencing; novel; phenotypic data; proliferative phase Menstrual cycle; reproductive; response; single nucleus RNA-sequencing; spatiotemporal; transcription factor

PROJECT SUMMARY/ABSTRACT Infertility occurs in approximately 15% of women of reproductive age in the United States. Approximately half of the cases involve impaired ovulation, the cause of which is often elusive. The aim of this project is to achieve new understanding of ovulatory defects that will serve as a foundation for effective treatment of infertility. It is known that obesity negatively impacts female fertility and ovulation, but the underlying mechanism remains to be elucidated. Recent findings highlight the crucial role of preovulatory ovarian vascular remodeling in successful ovulation: the ovulatory luteinizing hormone (LH) surge induces a series of vascular remodeling processes in the ovary, including changes in vascular permeability, vessel contraction and formation of new blood vessels. CCAAT/enhancer binding proteins alpha and beta (C/EBPα and C/EBPβ, jointly abbreviated C/EBPα/β) are rapidly induced in granulosa cells by the LH surge and function as important regulators of ovulation. Based on our preliminary data, which show the profound effects of C/EBPα/β deficiency on ovarian vascular remodeling in mice, we hypothesize that C/EBPα and C/EBPβ are key mediators by which the LH surge controls vascular remodeling in preovulatory ovaries. Given obesity’s negative impact on vascular function in general and on ovarian blood flow in women in particular, we also propose the novel concept that ovarian vascular remodeling is a key mediator between obesity and ovulation failure. This proposal first seeks to use murine models of ovulation failure and disrupted ovarian vascular remodeling to identify their regulatory mechanisms downstream of the LH surge, then addresses the knowledge deficit around obesity’s impact on ovarian vasculature. To achieve these goals we will apply 3-dimensional quantitative intravital imaging to a transgenic mouse line with ovary-specific ablation of C/EBPα/β to first define the specific vascular remodeling events regulated by C/EBPα/β in preovulatory ovaries, then determine in a diet-induced obese mouse model the impact of obesity on the activity of C/EBPα/β and vascular remodeling during ovulation. We will further seek understanding of cell type-specific mechanisms regulating preovulatory vascular remodeling and ovulation using single-cell, next-generation sequencing technologies; these approaches will also reveal whether epigenetic mechanisms regulating chromatin accessibility play a key role in preovulatory vascular remodeling and ovulation, and whether C/EBPα/β mediate this interaction. Successful completion of the proposed studies will advance our understanding of ovulation regulation and have a major impact by elucidating links among obesity, epigenetic regulation, and ovarian function, thus enabling improved treatment of many cases of female infertility.

项目总结/摘要 在美国，大约15%的育龄妇女患有不孕症。的大约一半 这些病例涉及排卵障碍，其原因往往是难以捉摸的。该项目的目的是实现 对排卵缺陷的新认识，将作为有效治疗不孕症的基础。是 已知肥胖对女性生育力和排卵有负面影响，但潜在的机制仍然是 被阐明。最近的研究结果强调了排卵前卵巢血管重构在成功治疗卵巢癌中的关键作用。 排卵：排卵促黄体生成激素（LH）激增诱导一系列血管重塑过程， 卵巢，包括血管通透性的变化，血管收缩和新血管的形成。 CCAAT/增强子结合蛋白α和β（C/EBPα和C/EBPβ，共同缩写为C/EBPα/β）是 在颗粒细胞中由LH峰快速诱导，并作为排卵的重要调节剂发挥作用。基于 我们的初步数据显示，C/EBPα/β缺乏对卵巢血管重构有深远的影响， 在小鼠中，我们假设C/EBPα和C/EBPβ是LH峰控制血管生成的关键介质， 排卵前卵巢的重塑。考虑到肥胖对血管功能的负面影响， 特别是女性卵巢血流，我们还提出了卵巢血管重构的新概念， 是肥胖和排卵障碍之间的关键媒介。该建议首先寻求使用小鼠模型， 排卵失败和破坏卵巢血管重塑，以确定其下游的调节机制 的LH激增，然后解决肥胖对卵巢血管系统的影响的知识赤字。到 为了实现这些目标，我们将对转基因小鼠系应用3维定量活体成像， 卵巢特异性C/EBPα/β消融，以首先确定由C/EBPα/β调节的特异性血管重塑事件 在排卵前卵巢中，然后在饮食诱导的肥胖小鼠模型中确定肥胖对活动的影响 排卵期C/EBPα/β与血管重构的关系。我们将进一步寻求对细胞类型特异性的理解， 使用单细胞、下一代、高密度聚乙烯（PEG）技术调节排卵前血管重塑和排卵的机制 测序技术;这些方法还将揭示表观遗传机制是否调节 染色质可及性在排卵前血管重构和排卵中起关键作用，C/EBPα/β 介导这种相互作用。成功完成拟议的研究将增进我们对 排卵调节，并通过阐明肥胖，表观遗传调节， 卵巢功能，从而使许多女性不孕症的治疗得到改善。

项目成果

A spatiotemporal molecular atlas of the ovulating mouse ovary.

• DOI: 10.1073/pnas.2317418121
• 发表时间: 2024-01-30
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Mantri, Madhav;Zhang, Hanxue Hannah;Spanos, Emmanuel;Ren, Yi A.;De Vlaminck, Andiwijn
• 通讯作者: De Vlaminck, Andiwijn