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: 10503652
• 负责人: YI REN
• 金额: $ 34.64万
• 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/10503652
• 关键词: 3-Dimensional; Ablation; Address; Affect; Age; Animals; Blood Vessels; Blood flow; CCAAT-Enhancer-Binding Protein-alpha; Cell Nucleus; Cells; Cellular Assay; Chromatin; Confocal Microscopy; 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 of activation protein; 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; base; cell type; constriction; 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; spatiotemporal; transcription factor; transcriptome sequencing

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.

项目摘要/摘要 在美国，大约有15％的生殖年龄妇女发生不育。大约一半 病例涉及排卵受损，其原因通常是弹性的。该项目的目的是实现 对排卵缺陷的新理解将是有效治疗不育的基础。这是 知道肥胖会对女性的生育和排卵产生负面影响，但潜在的机制仍然存在 阐明。最近的发现凸显了卵巢前血管重塑成功中至关重要的作用 排卵：排卵丽丝素化的马酮（LH）激增可引起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，共同缩写的C/EBPα/β） 通过LH激增，在颗粒细胞中迅速诱导的排卵调节剂。基于 我们的初步数据显示了C/EBPα/β缺乏对卵巢血管重塑的深远影响 小鼠，我们假设C/EBPα和C/EBPβ是关键的介体，LH激增控制血管 在卵巢前进行重塑。鉴于目标对总体和一般的血管功能的负面影响 尤其是女性的卵巢血流，我们还提出了卵巢血管重塑的新颖概念 是肥胖和排卵衰竭之间的关键调解因子。该建议首先试图使用 排卵衰竭和卵巢血管重塑，以识别其下游的调节机制 然后，LH激增，解决了围绕肥胖对卵巢脉管系统的影响的知识赤字。到 实现这些目标，我们将在具有的转基因小鼠系列中应用3维定量浸泡成像 C/EBPα/β的卵巢特异性消融首先定义由C/EBPα/β调节的特异性血管重塑事件 在卵巢前的卵巢中，然后在饮食引起的肥胖小鼠模型中确定肥胖对活动的影响 C/EBPα/β和排卵过程中的血管重塑。我们将进一步寻求特定细胞类型的理解 使用单细胞，下一代来调节排卵前血管重塑和排卵的机制 测序技术；这些方法还将揭示是否调节表观遗传机制 染色质可及性在排卵前的血管重塑和排卵中起关键作用，以及C/EBPα/β是否 调解这种相互作用。成功完成拟议的研究将提高我们对 排卵调节，并通过阐明肥胖，表观遗传调节和 卵巢功能，从而改善了许多女性不育症病例的治疗。