Signals controlling tissues homeostasis in the ovary

控制卵巢组织稳态的信号

• 批准号: 10421249
• 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/10421249
• 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; rapid testing; receptor; reproductive; response; stem cell self renewal; 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发展已经揭示了一种进化保守的途径 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。该途径称为 河马信号通路和破坏河马途径导致组织稳态的丧失和 有助于许多人类疾病。尽管在过去十年中对河马途径进行了广泛研究，但 调节河马途径的细胞外信号和膜受体的确切性质仍然难以捉摸。 最近的研究以及我们的初步数据表明，河马途径的效应子Yap和Taz， 在卵巢中起重要作用。卵巢是一个引人入胜的器官，可促进卵母细胞的成熟 以及性激素的产生，这对于成功的生殖和生活质量很重要。这 卵巢卵泡是卵巢的功能单位。原始卵泡的形成是关键的细胞过渡 过程;胎儿生命期间卵泡发生的失败导致卵巢发育不全和卵巢过早 失败。在女性中，早期卵巢功能的丧失不仅会导致不育，而且导致了 更年期有关的并发症。随着卵泡的发展，卵泡的颗粒和丘脑细胞增殖 并分泌性激素和局部因素，这些因素对于成功的卵母细胞至关重要。在女性和 牛在每个生殖周期中都会发生多个卵泡生长和闭锁。卵泡发展 当颗粒细胞和theca细胞分化为孕酮分泌的黄体细胞时，在排卵时终止。 孕酮对于发育胚胎，胚胎植入子宫至关重要， 维持怀孕。卵泡发生和黄体形成或功能的破坏导致不平衡 激素产生，早期胚胎衰竭以及可能导致发展的细胞的转化 肿瘤。考虑到与卵巢功能障碍相关的不孕症的妇女人数 了解调节卵泡发展，卵泡增殖和分化的机制， 黄体细胞的功能具有积极影响妇女健康的巨大潜力。我们有差距 了解河马途径对卵泡发育和卵巢细胞分化的贡献 颗粒和theca细胞，最终形成叶酸肠菌群。该提议将检验以下假设 卵泡发育需要YAP和TAZ，但主动河马信号传导有助于分化 颗粒和theca细胞。在此提案中，我们将利用可探讨的体内小鼠模型研究卵泡 开发和体外牛模型，研究卵泡细胞和黄体功能的增殖和分化。 牛是女性的绝佳典范 卵泡生成的波和卵形的波非常相似，黄体期的长度和妊娠相似 可以从牛获得足够量的组织和纯化的细胞种群。这项研究支持 我们充分了解控制卵泡发育和法体的机制的长期目标 功能。这项研究的短期目标是发现河马信号事件如何有助于卵泡 发育和细胞分化。拟议的研究有望提供有关有关的新信息 河马途径在调节卵巢功能中所扮演的角色，包括卵泡发育，卵母细胞 成熟和卵巢激素产生。该研究提案集中于识别 负责从外部环境传输信号到核的分子机制，启动 基因表达和复制，然后将分子反应转化为功能的变化， 分化。有超过220万的退伍军人和32％的女性接受VA医疗保健。 育龄的女性退伍军人正在以创纪录的数字在VA设施中寻求护理。理解 男女生殖健康和生物学都对改善健康和生活质量至关重要。