Sex-Specific Effects of Endocrine Disruption on Aging and Alzheimer's Disease

内分泌干​​扰对衰老和阿尔茨海默病的性别特异性影响

• 批准号: 9790887
• 负责人: VIRGINIA M MILLER
• 金额: $ 153.73万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9790887
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Ancillary Study; Area; Bilateral; Bilateral oophorectomy; Biological; Biological Markers; Biology; Cardiovascular Diseases; Categories; Cell Aging; Cells; Centers of Research Excellence; Cerebrovascular Disorders; Clinic; Clinical; Cognitive; Cognitive aging; Complement; Dementia; Disease; Doctor of Philosophy; Education; Endocrine disruption; Estrogen Replacement Therapy; Female; Foundations; Functional disorder; Funding; Future; Goals; Hormonal; Human; Impaired cognition; Investigation; Leadership; Long-Term Effects; Longevity; Malignant neoplasm of ovary; Measures; Menarche; Menopause; Modeling; Morbidity - disease rate; Mus; Outcome; Ovarian hormone; Ovariectomy; Pathology; Patient Recruitments; Phenotype; Physical Function; Plasma; Pregnancy; Premenopause; Process; Proteins; Recording of previous events; Research; Research Methodology; Research Training; Resources; Risk Factors; Salpingo-Oophorectomy; Sex Differences; Sexual Dysfunction; Skin Aging; Specialized Center; Testing; Tissues; Training; Training and Education; Translational Research; United States; Woman; Women' s Health; Work; adverse outcome; apolipoprotein E-4; base; cardiovascular disorder risk; career; cognitive function; design; experience; falls; frailty; gender difference; health difference; hormone therapy; imaging biomarker; innovation; interdisciplinary approach; interest; men; mortality; neuroimaging; pathological aging; pregnancy disorder; prophylactic; senescence; sex; translational approach; treatment response

OVERALL: SUMMARY/ABSTRACT Michelle M. Mielke, Ph.D. Aging-associated physical and cognitive decline and Alzheimer's disease (AD) are conditions that affect men and women differently across their lifespan. There are important sex and gender differences for these conditions, including risk factors, manifestations, response to treatments, morbidity, and mortality. The overarching theme of the Mayo Clinic Specialized Center of Research Excellence (SCORE) on Sex Differences is to investigate how abrupt loss of ovarian hormones, caused by bilateral salpingo-oophorectomy (BSO) prior to natural menopause, affects overall aging, physical and cognitive function, and risk for AD pathophysiology. Given the large number of aging women with a history of premenopausal BSO, there is an urgent need to understand the long-term physical and cognitive outcomes. In addition, we need new evidence to empower women considering prophylactic BSO to make more informed decisions in the future. The central hypothesis of our SCORE renewal is that the abrupt endocrine disruption caused by premenopausal BSO will accelerate pathological aging processes that manifest as reductions in physical and cognitive function and in AD pathophysiology. This hypothesis will be tested through three inter-related translational projects, which are supported by three inter-dependent Cores. Our interdisciplinary translational approach using both humans (Projects 1 and 2) and mice (Project 3) provides the foundation to: 1) establish the effects of abrupt endocrine disruption in women, 2) develop a more complete understanding of the biological mechanisms involved, 3) devise a targeted approach to identify and mitigate the adverse outcomes, 4) design future studies to mechanistically test whether targeting senescent cells mitigates the effects of accelerated aging in these women, and 5) empower women considering prophylactic BSO to make more informed decisions. Our rigorous approach is supported by an experienced leadership team through the Leadership Administrative Core, by a Resource Support Core - Clinical that will provide financial and operational efficiency for participant recruitment, and by a Career Enhancement Core that will provide career enrichment, leadership training, and funds to support ancillary studies of the main projects. These resources will stimulate new interest in sex differences and women's health. The Mayo Clinic SCORE will serve as a vital hub for education and dissemination of innovative sex-based translational research methods, results, and best practices. Our integrated approach for research, training, and education is consistent with the goals of the SCORE on Sex Differences RFA, and assures continuing research in areas of women's health and sex differences by training the work force of the future.

总结/摘要：米歇尔·M·米尔克，博士。 与衰老相关的身体和认知能力下降以及阿尔茨海默病(AD)是影响男性的疾病 而女性在一生中会有不同的表现。对于这些人来说，有重要的性别和性别差异 病情，包括危险因素、表现、治疗反应、发病率和死亡率。这个 梅奥诊所卓越研究专门中心(SCORE)的总体主题 不同之处在于调查双侧输卵管卵巢切除术如何造成卵巢激素的突然丢失 (BSO)在自然绝经之前，会影响整体衰老、身体和认知功能，以及AD的风险 病理生理学。鉴于大量有绝经前BSO病史的老年妇女，有 迫切需要了解长期的身体和认知结果。此外，我们还需要新的证据 使考虑预防性BSO的妇女能够在未来做出更明智的决定。中环 我们的评分更新假设是绝经前BSO引起的突然内分泌紊乱将 加速病理性衰老过程，表现为身体和认知功能的降低以及 AD病理生理学。这一假设将通过三个相互关联的翻译项目进行验证，这三个项目是 由三个相互依赖的核心支持。我们的跨学科翻译方法使用两个人类 (项目1和2)和MICE(项目3)提供了基础，以：1)建立突然内分泌的影响 女性精神分裂，2)对涉及的生物机制有更全面的了解，3) 设计一种有针对性的方法来识别和减轻不良后果，4)设计未来研究以 机械测试靶向衰老细胞是否能减轻这些细胞加速衰老的影响 妇女，以及5)使考虑预防性BSO的妇女能够做出更明智的决定。我们严谨的 该方法由经验丰富的领导团队通过领导力管理核心提供支持，由 资源支持核心-将为参与者提供财务和运营效率的临床 招聘，以及职业提升核心，将提供职业丰富、领导力培训和 用于支持主要项目的辅助研究的资金。这些资源将激起人们对性的新兴趣 差异和女性的健康。梅奥诊所的分数将成为教育和 传播创新的基于性别的翻译研究方法、结果和最佳实践。我们的 研究、培训和教育的综合方法与性行为评分的目标一致 差异RFA，并通过培训确保妇女健康和性别差异领域的持续研究 未来的劳动力。