BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10360744
• 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/10360744
• 关键词: Acute; Address; Adult; Affect; Age; Aging; Amenorrhea; Automobile Driving; Award; Basic Science; Biological; Bone Density; Cancer Science; 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; Ensure; 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; Proteomics; Publications; Publishing; Quality of life; Reporting; Reproduction; Reproductive Health; Reproductive History; Reproductive system; Research; Rodent; Role; Science; Scientist; Serous; Services; 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; 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.

妇女参与军队的参与率提高正在重塑退伍军人人口，妇女 构成VA医疗保健系统中增长最快的使用者之一。超过220万 妇女退伍军人和32％的人被招募接受VA医疗保健。妇女的军事经验和回应 对于这些经历，通常与男性不同，对他们的医疗保健需求，服务，质量， 以及整个人生过程中的结果。这是了解女退伍军人健康的独特方面 医疗保健对于确保这一重要人群获得以患者为中心的最高护理至关重要。 育龄的女性退伍军人正在VA设施寻求护理。早产卵巢衰竭，多囊性 卵巢综合征和原发性闭经（女性不育症的三个主要原因）与 卵巢异常功能。考虑到类固醇激素在健康中的重要性， 衰老和疾病，重要的是要清楚地了解控制卵巢的机制 为了解决困扰退伍军人的疾病过程的功能。一些与 卵巢类固醇生成的疾病是高血压，糖尿病，高胰岛素血症，肥胖，不育， 闭经，多囊卵巢综合征，与年龄相关的神经功能和骨质疏松症以及肿瘤 乳房，卵巢和子宫。申请人的研究计划将导致对卵巢的新理解 能够告知控制卵巢功能的方法的功能，该功能转化为改进的方法 仅生殖健康，但整体健康和寿命。此外，在 申请人的实验室改善了开发安全，有效，廉价，可逆和可接受的努力 男性和女性的避孕方法。申请人研究的一个方面探讨了 最近发现的河马信号传导途径控制卵巢发育中组织稳态的稳态， 内分泌功能和病理。这项研究表明，该途径对于正常 卵巢叶的开发和重新编程颗粒细胞通过关键转录调节剂在此中 途径（YAP1）导致癌症的发展。 YAP促进成年颗粒细胞肿瘤；它也调节 高级浆液性癌倡议和进展。进一步的VA研究将提供证据，以揭示 河马途径在植物形成，颗粒和theca细胞的分化中的作用， 和黄体细胞的功能。研究计划的另一个作用是了解衰老的各个方面 垂体性腺轴与改善健康和生活质量有关。衰老与损失有关 生殖潜力不仅反映了性腺功能的丧失，而且还反映了骨密度的损失， 心血管健康和心理功能。生殖健康的基础研究可以改善诊断和 治疗生殖健康状况，例如在老年退伍军人中发生的健康状况。另一个目标 该研究计划旨在阐明基本机制和代谢途径 有效的类固醇生成，以及这些途径的调节如何影响卵巢黄体功能和命运。短的 术语目标是确定由时间依赖的代谢，转录组和蛋白质组学变化。 控制曲折的命运的骑手。这些“ OMIC”分析结果的整合将允许 识别与黄体功能中断有关的新途径，并使我们更深入地了解 事件不仅是由营养骑士介导的，而且还由炎症介体介导。因为Luteum 对于所有哺乳动物物种的怀孕至关重要，这些发现将 贡献新信息以制定方法，包括具有特定代谢物的治疗方法，以减轻 肥胖和随之而来的炎症介质对生育能力的负面影响。潜在的好处是 由于生殖问题/治疗方法，改善了生活质量，成本降低和休息时间减少。全部 退伍军人可以从与复制健康有关的科学中受益。