BLRD Research Career Scientist Award Application

点击翻译按钮获取中文摘要

The increased rate of participation of women in the military is reshaping the Veteran population, with women constituting one of the fastest growing groups of users of the VA healthcare system. There are over 2.2 million women Veterans and 32% are enrolled to receive VA health care. Women’s military experiences, and responses to those experiences, are often distinct from men’s, with implications for their healthcare needs, services, quality, and outcomes throughout the life course. Thus, understanding the unique facets of women Veterans’ health and health care is critical to ensure that this important population receives the highest quality patient-centered care. Female Veterans of childbearing age are seeking care at VA facilities. Premature ovarian failure, polycystic ovary syndrome and primary amenorrhea, three major causes of female infertility, are associated with abnormal functioning of the ovary. Considering the widespread importance of steroid hormones in health, aging and disease, it is important to have a clear understanding of the mechanisms controlling ovarian function in order to address disease processes afflicting Veterans. Some metabolic disorders associated with disorders of ovarian steroidogenesis are hypertension, diabetes, hyperinsulinemia, obesity, infertility, amenorrhea, polycystic ovary syndrome, age-related neural function and osteoporosis, and neoplasms of the breast, ovary and uterus. The applicant’s research program will lead to new understanding of ovarian function that informs approaches to control ovarian function that translate into approaches that improve not only reproductive health, but overall health and longevity. Additionally, basic research such conducted in the applicant’s laboratory improves efforts to develop safe, effective, inexpensive, reversible, and acceptable contraceptive methods for males and females. One facet of the applicant’s research explores the role of the recently discovered Hippo signaling pathway that controls tissue homeostasis in ovarian development, endocrine function and pathology. This research demonstrates that this pathway is essential for normal ovarian follicle development and reprogramming of granulosa cells by a key transcriptional regulator in this pathway (YAP1) leads to development of cancer. YAP promotes adult granulosa cell tumors; it also regulates high-grade serous carcinoma initiation and progression. Further VA research will provide evidence to reveal the role of the Hippo pathway in follicle formation, proliferation and differentiation of granulosa and theca cells, and function of luteal cells. Another thrust of the research program is to understand aspects of the aging pituitary gonadal axis as it relates to improving health and quality-of-life. Aging is associated with a loss in reproductive potential, which not only reflects a loss of gonadal function, but also a loss of bone density, cardiovascular health and mental function. Basic research in reproductive health can improve diagnosis and treatment of reproductive health conditions such as those that occur in aging Veterans. Another goal of this research program is to elucidate the fundamental mechanisms and metabolic pathways essential for efficient steroidogenesis, and how modulation of those pathways affect ovarian luteal function and fate. Short term goals are to determine the time-dependent metabolic, transcriptomic, and proteomic changes induced by hormones that control the fate of the corpus luteum. Integration of results of these “omics” analyses will allow identification of new pathways involved in the disruption of luteal function and give us deeper insight into the events mediated not only by trophic hormones but also by inflammatory mediators. Because the corpus luteum is crucial for the establishment and maintenance of pregnancy in all mammalian species, these findings will contribute new information to formulate approaches, including treatments with specific metabolites, to mitigate the negative effects of obesity and attendant inflammatory mediators on fertility. Potential benefits are improved quality-of-life with reduced costs and less time off due to reproductive issues/treatments. All Veterans can benefit from science related to reproductive health.