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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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&apos 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

项目摘要

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.

总体而言：摘要/摘要 Michelle M. Mielke 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) 是影响男性的疾病女性在一生中的表现也有所不同。这些人之间存在重要的性别差异状况，包括危险因素、表现、对治疗的反应、发病率和死亡率。这梅奥诊所卓越研究专业中心 (SCORE) 的总体主题是性差异在于研究双侧输卵管卵巢切除术引起的卵巢激素突然丧失是如何发生的 (BSO) 在自然绝经之前，影响整体衰老、身体和认知功能以及 AD 风险病理生理学。鉴于大量老年女性有绝经前 BSO 病史，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 的女性能够在未来做出更明智的决定。中央我们的 SCORE 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下降以及 AD病理生理学。这一假设将通过三个相互关联的转化项目进行检验，它们是由三个相互依赖的核心支持。我们使用人类的跨学科转化方法（项目 1 和 2）和小鼠（项目 3）为以下方面提供了基础：1) 确定内分泌突变的影响对女性的破坏，2) 对所涉及的生物机制有更全面的了解，3) 设计有针对性的方法来识别和减轻不良后果，4）设计未来的研究从机制上测试针对衰老细胞是否可以减轻这些细胞中加速衰老的影响女性，5) 赋予考虑预防性 BSO 的女性做出更明智的决定。我们严谨的该方法由经验丰富的领导团队通过领导行政核心提供支持，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，该核心将提供职业丰富、领导力培训和资金用于支持主要项目的辅助研究。这些资源将激发人们对性的新兴趣差异和妇女健康。梅奥诊所 SCORE 将成为教育和培训的重要中心传播基于性别的创新转化研究方法、成果和最佳实践。我们的研究、培训和教育的综合方法与 SCORE on Sex 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。