Regulation of Angiogenesis in Mammalian Ovaries

我的实验室的长期目标是了解家畜卵巢功能的生物学，以及卵巢功能障碍如何导致生殖障碍和不孕。 该计划的短期目标是确定小RNA在调节卵巢中的血管形成、卵泡和黄体发育中的作用。 我的实验室一直在研究调节卵巢血管形成的因素以及这些因素如何影响正常和异常的卵巢功能方面处于领先地位。我们是第一个描述卵巢周期中促血管生成因子和抗血管生成因子之间的复杂关系，以及这种关系如何促进卵泡和黄体发育的。特别是，我们已经全面描述了血管内皮生长因子(VEGF)和血栓反应蛋白-1(TSP-1)家族在调控卵巢血管生成、卵泡和黄体发育以及生育方面的作用。在这项建议中，我们描述了一种方法来研究microRNAs在调节与卵巢血管生成、发育和功能相关的因子的表达中的作用，以及miRNAs如何参与牛囊性卵巢疾病(COD)等基于卵巢的生殖疾病。MmiRNAs是一种小的、非编码的RNAs，通过靶向信使RNAs(MRNAs)的3‘未翻译(3’UTRs)在转录后抑制基因表达，并已被证明调节一系列关键的生物过程。由于单个miRNA可以靶向多个mRNAs，而多个miRNAs也可能靶向单个mRNAs，因此microRNAs对基因表达具有显著的控制作用。 我们推测miRNAs在调节卵巢功能、协调卵巢血管生成和卵泡发育中是不可或缺的，而miRNA表达的改变有助于牛卵巢功能障碍和生殖障碍的发生和发展。 我们的研究计划被组织成三个主要目的来检验这一假说。目的1.鉴定参与调控卵巢血管生成的microRNAs的表达。目的2.评价microRNAs在调节卵巢血管生成、卵泡发育和黄体发育中的作用。目的3.确定microRNAs在卵巢基础生殖障碍中的作用。 影响：这些研究的结果将提供关于调控卵巢血管生成以及卵泡和黄体发育的生物学机制的新数据。虽然已经描述了促血管生成因子和抗血管生成因子的表达变化，但目前对这些因子是如何调节的，特别是它们如何相互抑制彼此的表达缺乏了解。这些研究的数据将阐明miRNAs在调控卵巢血管生成中的作用，以及它们如何促进牛的正常卵巢功能和卵巢病理(如COD)。

TheLong Term Objective of my lab is to understand the biology of ovarian function in domestic animals and how ovarian dysfunction can contribute to reproductive disorders and infertility. The Short Term Objective of this program is to identify the role of small RNAs in regulating blood vessel formation and follicle and luteal development in the ovary. My laboratory has been a leader in the study of factors that regulate blood vessel formation in the ovary and how these factors contribute to normal and abnormal ovarian function.  We were the first to describe the intricate relationship between pro- and anti-angiogenic factors throughout the ovarian cycle, and how this relationship contributes to follicular and luteal development. In particular, we have comprehensively described the roles of the vascular endothelial growth factor (VEGF) and thrombospondin-1 (TSP-1) families in regulating ovarian angiogenesis, follicular and luteal development, and fertility.  In this proposal, we describe an approach to study the role of microRNAs in mediating the expression of factors related to ovarian angiogenesis, development, and function, and how miRNAs may be involved in ovarian-based reproductive disorders such as cystic ovarian disease (COD) in cattle.  MiRNAs are small, non-coding RNAs that repress gene expression post-transcriptionally by targeting 3’ untranslated (3’UTRs) of messenger RNAs (mRNAs) and have been shown to regulate a host of critical biological processes.  MicroRNAs have significant control over gene expression, as a single miRNA can target multiple mRNAs, and multiple miRNAs may also target a single mRNA. We hypothesize that miRNAs are integral to the regulation of ovarian function and coordinate ovarian angiogenesis and follicular development, and altered miRNA expression contributes to the onset and progression of ovarian dysfunction and reproductive disorders in bovines. Our research program is organized into three main Aims to test this hypothesis.  Aim 1. Identify the expression of microRNAs involved in regulating ovarian angiogenesis. Aim 2. Evaluate the role of microRNAs in regulating ovarian angiogenesis, and follicular and luteal development.  Aim 3. Determine the role of microRNAs in ovarian-based reproductive disorders. Impact: The results from these studies will provide new data about the biological mechanisms that regulate ovarian angiogenesis and follicular and luteal development. Although changes in expression of pro- and anti-angiogenic factors have been described, there currently is a significant lack of understanding of how these factors are regulated, particularly in how they reciprocally inhibit each other’s expression. The date from these studies will illuminate the roles of miRNAs in regulation ovarian angiogenesis and how they contribute to normal ovarian function and ovarian pathologies such as COD in cattle.