BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10512068
• 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: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2028-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10512068
• 关键词: Acute; Address; Adult; Affect; Age; Aging; Amenorrhea; Automobile Driving; Award; Basic Science; Biological; Bone Density; Carbohydrates; Carcinoma; Cattle; Cell Proliferation; Cells; Centers for Disease Control and Prevention (U.S.); Clinical Endocrinology; Contraceptive methods; Cyclic AMP-Dependent Protein Kinases; Development; Diabetes Mellitus; Diagnosis; Disease; Endocrine; Endocrinology; Enrollment; Event; Exhibits; Feedback; Female; Female infertility; Fertility; Follicle Stimulating Hormone Receptor; Genetic Transcription; Goals; Health; Healthcare; Healthcare Systems; Homeostasis; Hormones; Human; Human Follicle Stimulating Hormone; Hyperinsulinism; Hypertension; In Vitro; Infertility; Inflammation Mediators; Journals; Knowledge; LATS2 gene; Laboratories; Life Cycle Stages; Lipids; Longevity; Luteal Cells; Maintenance; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of ovary; Mammary Neoplasms; Manuscripts; Mediating; Menopause; Menstruation Disturbances; Metabolic; Metabolic Diseases; Metabolic Pathway; Military Personnel; Mitochondria; Molecular; Molecular Medicine; Molecular Weight; Neurophysiology - biologic function; Obesity; Oncogenes; Oocytes; Osteoporosis; Outcome; Ovarian; Ovarian Diseases; Ovarian Follicle; Ovary; Pathology; Pathway interactions; Patient-Centered Care; Pituitary Gland; Polycystic Ovary Syndrome; Population; Pregnancy Maintenance; Premature Ovarian Failure; Process; Production; Progesterone; Proliferating; Proteomics; Publications; Publishing; Quality of life; Reporting; Reproduction; Reproductive Health; Reproductive History; Reproductive system; Research; Rodent; Role; Science; Scientist; Serous; Services; Shapes; Signal Pathway; Signal Transduction; Steroid biosynthesis; Steroids; Time; Tissues; Translating; United States; United States Department of Agriculture; United States National Institutes of Health; Uterine Neoplasms; Variant; Veterans; Woman; Women' s Health; Work; age related; aged; bone loss; cancer cell; cancer initiation; cardiovascular health; care seeking; career; child bearing; cholesterol trafficking; corpus luteum; cost; endometriosis; experience; glycosylation; gonad function; granulosa cell; granulosa cell tumor; improved; in vitro Model; in vivo; insight; male; member; men; mental function; migration; military veteran; military women; older women; operation; ovarian neoplasm; pituitary gonadal axis; primary amenorrhea; programs; receptor binding; reproductive; response; senescence; steroid hormone; theca cell; transcriptomics; tumor progression; young woman

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.

女性参军比例的提高正在重塑退伍军人群体，其中女性 构成了退伍军人医疗保健系统增长最快的用户群体之一。有超过220万人 女性退伍军人和32%的人登记接受退伍军人医疗保健。女性的军事经历和回应 这些体验往往有别于男性，对他们的医疗需求、服务、质量、 以及整个生命过程中的结果。因此，了解女性退伍军人健康和 卫生保健是确保这一重要人群得到以患者为中心的最高质量护理的关键。 育龄女性退伍军人正在退伍军人管理局寻求护理。卵巢早衰，多囊 卵巢综合征和原发闭经是女性不孕的三个主要原因，与 卵巢功能不正常。考虑到类固醇激素在健康中的广泛重要性， 衰老和疾病，重要的是要清楚地了解控制卵巢的机制 为解决困扰退伍军人的疾病进程而发挥作用。一些与以下相关的代谢紊乱 卵巢类固醇激素生成障碍有高血压、糖尿病、高胰岛素血症、肥胖、不孕症、 闭经、多囊卵巢综合征、年龄相关神经功能和骨质疏松症以及卵巢肿瘤 乳房、卵巢和子宫。申请者的研究计划将导致对卵巢的新理解 为控制卵巢功能的方法提供信息的功能，这些方法转化为不会改善的方法 只有生殖健康，但总体健康和长寿。此外，这类基础研究是在 申请人的实验室改进努力，开发安全、有效、廉价、可逆和可接受的 男女避孕方法。申请者研究的一个方面是探索 最近发现了控制卵巢发育中组织动态平衡的河马信号通路， 内分泌功能和病理学。这项研究表明，这一途径对于正常 卵巢卵泡发育和颗粒细胞重编程的关键转录调控因子 途径(YAP1)导致癌症的发生。YAP促进成人颗粒细胞瘤；它还调节 高级别浆液性癌的发生和发展。进一步的退伍军人事务部研究将提供证据来揭示 河马途径在颗粒细胞和膜细胞卵泡形成、增殖和分化中的作用 和黄体细胞的功能。研究计划的另一个重点是了解衰老的各个方面 垂体性腺轴，因为它关系到改善健康和生活质量。衰老与身体健康的损失有关 生殖潜力，这不仅反映了性腺功能的丧失，也反映了骨密度的丧失， 心血管健康和心理功能。生殖健康的基础研究可以提高诊断和 生殖健康疾病的治疗，例如发生在老年退伍军人身上的疾病。另一个目标是 这项研究计划是为了阐明基本机制和代谢途径必不可少的 有效的类固醇合成，以及这些途径的调节如何影响卵巢黄体功能和命运。短的 学期目标是确定与时间相关的代谢、转录和蛋白质组学变化。 控制黄体命运的荷尔蒙。整合这些“组学”分析的结果将使 识别参与黄体功能紊乱的新途径，并使我们更深入地了解 这些事件不仅由营养激素调节，而且还由炎症介质调节。因为黄体 对所有哺乳动物的妊娠的建立和维持至关重要，这些发现将 提供新的信息以制定方法，包括使用特定代谢物的治疗，以缓解 肥胖及其伴随的炎症介质对生育的负面影响。潜在的好处是 提高生活质量，降低成本，减少因生殖问题/治疗而休假的时间。全 退伍军人可以从与生殖健康相关的科学中受益。