Signals controlling tissues homeostasis in the ovary

控制卵巢组织稳态的信号

• 批准号: 9780784
• 负责人: JOHN S DAVIS
• 金额: --
• 依托单位: OMAHA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9780784
• 关键词: Affect; Age; Apoptosis; Biological Models; Cattle; Cell Cycle; Cell Differentiation process; Cell Nucleus; Cell Proliferation; Cell Survival; Cells; Complex; Cyclic AMP-Dependent Protein Kinases; Data; Development; Diagnosis; Disease; Embryo; Embryonic Development; Endocrine; Enrollment; Environment; Estrogens; Event; Failure; Female; Fertility; Gene Expression; Goals; Gonadal Steroid Hormones; Granulosa-Lutein Cells; Growth; Health; Healthcare; Homeostasis; Homologous Gene; Hormone imbalance; In Vitro; Infertility; Knowledge; Length; Life; Light; Longevity; Luteal Cells; Luteal Phase; Membrane; Menopause; Menstruation Disturbances; Modeling; Molecular; Mus; Nature; Nuclear; Nuclear Export; Organ; Organ Size; Osteoporosis; Ovarian; Ovarian Follicle; Ovarian Granulosa Cell; Ovarian hormone; Ovary; Ovulation; Pathway interactions; Pattern; Pharmacology; Phosphorylation; Phosphotransferases; Play; Population; Pregnancy; Pregnancy Maintenance; Premature Ovarian Failure; Primordial Follicle; Process; Production; Progesterone; Proliferating; Protein-Serine-Threonine Kinases; Quality of life; Regulation; Reproduction; Reproductive Biology; Reproductive Health; Research; Research Proposals; Research Support; Role; Signal Pathway; Signal Transduction; Signaling Protein; Steroids; Testing; Theca-Lutein Cells; Tissue Recombination; Tissues; Transcription Coactivator; Translating; Tumor Suppression; Tumor Suppressor Proteins; Uterus; Veterans; Woman; Women' s Health; aged; care seeking; cell growth; cell transformation; child bearing; corpus luteum; endometriosis; extracellular; fascinate; fetal; folliculogenesis; genetic regulatory protein; granulosa cell; human disease; improved; in vivo; knock-down; men; mouse model; natural Blastocyst Implantation; novel; oocyte maturation; ovarian dysfunction; receptor; reproductive; response; self-renewal; stem cells; steroid hormone; theca cell; transcription factor; tumor

Recent developments in other fields of research have shed light on an evolutionarily conserved pathway that controls organ size by regulating cell proliferation, apoptosis, and stem cell self-renewal. This pathway is called the Hippo signaling pathway and disrupting the Hippo pathway results in the loss of tissue homeostasis and contributes to many human diseases. Despite extensive study of the Hippo pathway in the past decade, the exact nature of extracellular signals and membrane receptors regulating the Hippo pathway remains elusive. Recent studies and our preliminary data demonstrate that YAP and TAZ, the effectors of the Hippo pathway, play an important role in the ovary. The ovary is a fascinating organ that contributes the maturation of oocytes and the production of sex hormones, which are important for successful reproduction and quality-of-life. The ovarian follicle is the functional unit of the ovary. The formation of primordial follicles is a critical cellular transition process; and the failure of folliculogenesis during fetal life leads to ovarian dysgenesis and premature ovarian failure. In women the early loss of ovarian function not only causes infertility but also contributes to the onset of menopause-related complications. The granulosa and theca cells of the follicle proliferate as the follicle develops and secrete sex hormones and local factors that are critical for successful oocyte maturation. In women and cattle multiple waves of follicle growth and atresia occur during each reproductive cycle. Follicle development terminates at ovulation when the granulosa and theca cells differentiate into progesterone secreting luteal cells. Progesterone is essential for development of the embryo, implantation of the embryo into the uterus and maintenance of pregnancy. Disruption of folliculogenesis and luteal formation or function results in imbalanced hormone production, early embryonic failure, and possibly the transformation of cells leading to the development of tumors. Considering the number of women who suffer from infertility associated with ovarian dysfunction, understanding mechanisms that regulate the development of follicles, proliferation and differentiation of follicles, and the function of luteal cells holds great potential to positively impact women's health. There is a gap in our knowledge of the contributions of the Hippo pathway to follicle development and cellular differentiation of ovarian granulosa and theca cells which ultimately form the corpus luteum. This proposal will test the hypothesis that YAP and TAZ are required for follicle development but active Hippo signaling contributes to the differentiation of granulosa and theca cells. In this proposal we will utilize a tractable in vivo mouse model to study follicle development and an in vitro cow model to study proliferation and differentiation of follicle cells and luteal function. Cows are an excellent model for women because cows, like women, are mono-ovulatory, the endocrine profile and waves of folliculogenesis are remarkably similar, the length of the luteal phase and pregnancy are similar and adequate amounts of tissue and purified cell populations can be obtained from cows. This research supports our long-term objectives to fully understand the mechanisms controlling follicle development and corpus luteum function. The short-term goals of this research are to discover how Hippo signaling events contribute to follicle development and cellular differentiation. The proposed studies are expected to provide new information about the role played by the Hippo pathway in regulation of ovarian function, including follicle development, oocyte maturation, and ovarian hormone production. This research proposal centers on the identification of the molecular mechanisms responsible for transmitting signals from the outside environment to the nucleus, initiating gene expression and replication, and then translating molecular responses into changes in function and differentiation. There are over 2.2 million women Veterans and 32% are enrolled to receive VA health care. Female Veterans of childbearing age are seeking care at VA facilities in record numbers. Understanding reproductive health and biology for both men and women is crucial to improving health and quality-of-life.

其他研究领域的最新进展揭示了一条进化上保守的途径， 通过调节细胞增殖、凋亡和干细胞自我更新来控制器官大小。这条路径被称为 Hippo 信号通路和 Hippo 通路的破坏会导致组织稳态的丧失 导致许多人类疾病。尽管过去十年对 Hippo 通路进行了广泛的研究， 调节 Hippo 通路的细胞外信号和膜受体的确切性质仍然难以捉摸。 最近的研究和我们的初步数据表明，Hippo 通路的效应子 YAP 和 TAZ， 在卵巢中发挥重要作用。卵巢是一个令人着迷的器官，有助于卵母细胞的成熟 以及性激素的产生，这对于成功繁殖和生活质量非常重要。这 卵泡是卵巢的功能单位。原始卵泡的形成是关键的细胞转变 过程;胎儿时期卵泡发生失败会导致卵巢发育不全和卵巢早熟 失败。对于女性来说，卵巢功能过早丧失不仅会导致不孕，还会导致不孕症的发生。 更年期相关的并发症。卵泡的颗粒细胞和卵泡膜细胞随着卵泡的发育而增殖 并分泌对卵母细胞成功成熟至关重要的性激素和局部因子。在女性和 牛在每个生殖周期中都会发生多波卵泡生长和闭锁。卵泡发育 当颗粒细胞和卵泡膜细胞分化为分泌孕酮的黄体细胞时，排卵终止。 黄体酮对于胚胎的发育、胚胎植入子宫以及 维持妊娠。卵泡发生和黄体形成或功能的破坏导致失衡 激素产生、早期胚胎失败以及可能导致发育的细胞转化 肿瘤。考虑到因卵巢功能障碍而患有不孕症的女性人数， 了解调节卵泡发育、卵泡增殖和分化的机制， 黄体细胞的功能具有对女性健康产生积极影响的巨大潜力。我们之间存在差距 了解 Hippo 途径对卵泡发育和卵巢细胞分化的贡献 最终形成黄体的颗粒细胞和卵泡膜细胞。该提案将检验以下假设： YAP 和 TAZ 是卵泡发育所必需的，但活跃的 Hippo 信号传导有助于卵泡的分化 颗粒细胞和卵泡膜细胞。在本提案中，我们将利用易于处理的体内小鼠模型来研究卵泡 开发和体外牛模型来研究卵泡细胞的增殖和分化以及黄体功能。 奶牛是女性的绝佳典范，因为奶牛和女性一样，是单排卵的，内分泌特征 卵泡发生的波数非常相似，黄体期和妊娠的长度也相似 可以从奶牛身上获得足够量的组织和纯化的细胞群。这项研究支持 我们的长期目标是充分了解控制卵泡发育和黄体的机制 功能。这项研究的短期目标是发现 Hippo 信号事件如何促进卵泡 发育和细胞分化。拟议的研究预计将提供有关以下方面的新信息： Hippo 通路在卵巢功能调节中的作用，包括卵泡发育、卵母细胞 成熟和卵巢激素的产生。本研究计划的重点是确定 负责将信号从外部环境传递到细胞核的分子机制，启动 基因表达和复制，然后将分子反应转化为功能和复制的变化 差异化。有超过 220 万女性退伍军人，其中 32% 登记接受 VA 医疗保健。 育龄女性退伍军人在退伍军人管理局机构寻求护理的人数创历史新高。理解 男性和女性的生殖健康和生物学对于改善健康和生活质量至关重要。