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.
