MicroRNA Regulation of Ovarian Function

MicroRNA 对卵巢功能的调节

基本信息

批准号：
8676490
负责人：
LANE K. CHRISTENSON
金额：
$ 29.64万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8676490
关键词：
Affect Age Animal Model Apoptosis Applications Grants Binding CCAAT-Enhancer-Binding Proteins Cell Differentiation process Cell physiology Competence Contraceptive Agents Contraceptive methods Data Data Set Defect Development Electrophoretic Mobility Shift Assay Enzymes Event Fertility Functional disorder Gene Chips Gene Expression Gene Expression Regulation Gene Targeting Genes Goals Hypertrophy Infertility Knockout Mice Knowledge Laboratories Link Luteinization Luteinizing Hormone Mediating Meiosis Messenger RNA MicroRNAs Molecular Mus Oocytes Outcome Ovarian Ovarian Granulosa Cell Ovarian Tissue Ovary Ovulation Pathway interactions Physiological Physiological Processes Physiology Play Positioning Attribute Post-Transcriptional Regulation Principal Investigator Process Progesterone Receptors Proteomics Publications Quality of life Recruitment Activity Regulation Reproductive Health Research Research Personnel Role Short luteal phase Signal Transduction Somatic Cell Syndrome System Techniques Testing Therapeutic Intervention Time Tissues Transcript Translations Woman Work analytical method base cell growth chromatin immunoprecipitation corpus luteum experience granulosa cell high throughput analysis improved in vivo in vivo Model innovation mathematical model promoter protein expression public health relevance receptor reproductive reproductive success research study response transcription factor treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Contraception and infertility are two major quality of life issues facing women of reproductive age. Ovulation of a fertilizable oocyte and formation of a functional corpus luteum are absolute requirements for reproductive success and are induced by the mid-cycle surge of luteinizing hormone (LH). Disrupted LH actions are a leading cause of infertility and a target of many contraceptive methods. Numerous studies have characterized the signaling cascades and transcriptional responses downstream of LH action; and dramatic progress in our understanding of how LH and its receptor are able to regulate such complicated physiological processes such as ovulation, resumption of meiosis and luteinization have resulted. However, significant questions still remain unsolved or unexplored, including the role post-transcriptional regulation of gene expression plays in mediating LH action. Our recent studies with Dicer1 deficient mice have implicated post-transcriptional and specifically microRNA mediated gene regulation as playing a key role in ovulation. We have also identified miR-21 as an LH- induced microRNA (miRNA) within granulosa cells of the periovulatory follicle, and demonstrated that it suppresses apoptosis and enhances granulosa cell hypertrophy by promoting global translation. Furthermore, our current in vivo studies demonstrate that loss of miR-21 decreases ovulation rate. Therefore, the central hypothesis of this proposal is that miR-21 plays critical roles in the LH-induced ovarian function. To test this central hypothesis, in Specific Aim1, we determine the function of miR-21 within periovulatory follicular granulosa cells and its role in ovulation, luteinization and oocyte competence. In Specific Aim 2, we identify the target transcripts and molecular pathways miR-21 regulates within periovulatory granulosa cells, while in Specific Aim 3 we determine which LH-induced transcription factors modulate miR-21 gene expression. The studies proposed in this grant application will define a subset of genes regulated by miR-21 mediated post-transcriptional gene regulation and will functionally link this miRNA with physiologic and developmental events critical to ovarian function. The long-term benefits of this research will enhance our understanding of the ovary, ultimately impacting the development of treatment strategies for infertility and new contraceptive methods for women.

描述（由申请人提供）：避孕和不育是生殖年龄妇女面临的两个主要生活质量问题。可肥大的卵母细胞的排卵和功能性鳞状的形成是生殖成功的绝对要求，并由黄体生成激素（LH）的中期循环激增诱导。 LH作用破坏是不孕症的主要原因，也是许多避孕方法的目标。许多研究表征了LH作用下游的信号级联和转录响应。以及我们对LH及其受体如何能够调节复杂生理过程（例如排卵，减数分裂恢复和黄体化等复杂的生理过程）的理解方面的巨大进步。然而，重要的问题仍然未解决或未探索，包括基因表达在介导LH作用中扮演的角色调节。我们最近对DICER1缺乏小鼠的研究暗示了转录后，特别是microRNA介导的基因调节是在排卵中起关键作用。我们还确定了miR-21是卵泡周围粒细胞内的LH诱导的microRNA（miRNA），并证明它通过促进全球翻译来抑制凋亡并增强颗粒细胞肥大。此外，我们目前的体内研究表明，miR-21的损失会降低排卵率。因此，该提议的核心假设是miR-21在LH诱导的卵巢功能中起关键作用。为了检验该中心假设，在特定的AIM1中，我们确定了卵泡周围卵泡颗粒细胞中miR-21的功能及其在排卵，黄体化和卵母细胞能力中的作用。在特定的目标2中，我们确定了靶转录本和分子途径miR-21调节卵巢颗粒细胞内的调节，而在特定目标3中，我们确定了哪些LH诱导的转录因子调节miR-21基因表达。本赠款应用中提出的研究将定义由miR-21介导的转录后基因调控调节的基因的子集，并将该miRNA与对卵巢功能至关重要的生理和发育事件联系起来。这项研究的长期好处将增强我们对卵巢的理解，最终影响不孕症的治疗策略和妇女的新避孕方法。