Sex Hormones, Aging, Alzheimer's Disease and Other Neurodegenerative Diseases in Women

女性的性激素、衰老、阿尔茨海默病和其他神经退行性疾病

• 批准号: 10222546
• 负责人: Cynthia Diana Johanna Kusters
• 金额: $ 8.05万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222546
• 关键词: Acceleration; Address; Age; Age of Onset; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Animals; Biometry; Blood; Brain; Cell Line; Characteristics; Clinical Trials; Collaborations; DNA Methylation; Data; Data Set; Development; Disease; Disease Progression; Elderly; Ensure; Epidemiology; Epigenetic Process; Estrogens; Exposure to; Female; General Population; Genes; Genetic; Goals; Gonadal Steroid Hormones; Hormone use; Hormones; Human; Huntington Disease; Impaired cognition; Life Cycle Stages; Literature; Longevity; Measures; Mediation; Methods; Methylation; Motor; Nerve Degeneration; Neurodegenerative Disorders; Neurology; Observational Study; Parkinson Disease; Pathology; Patients; Phenotype; Population; Postmenopause; Progesterone; Questionnaires; Registries; Reproductive History; Research; Risk; Risk Factors; Role; Testosterone; Time; Training; Validation; Woman; age related neurodegeneration; base; brain tissue; clinical trial analysis; disability; epigenetic marker; experience; gender difference; genome wide association study; healthy aging; hormone therapy; interdisciplinary approach; mild cognitive impairment; mortality; reproductive; reproductive hormone; therapeutic target; whole genome

Abstract As the general population ages, understanding the factors that contribute to longevity, healthy aging, and disability is paramount. Sex hormones (SH) have been hypothesized to be one of the possible reasons for the gender difference in both longevity and neurodegenerative disorders (ND).13 SH, specifically estrogen, progesterone and testosterone) have shown neuroprotective effects in animal and cell-line studies,14–16 and in disease-related animal models for Alzheimer’s Disease,17–24 Parkinson’s Disease,25–29 and Huntington’s Disease.30–35 Previous studies analyzing the effect of sex hormones (reproductive history or hormone metabolizing genes) on ND and longevity in human observational studies have been inconclusive. 36–104 Also inconsistent have been the clinical trials that analyzed whether postmenopausal hormone therapy had a positive effect on ND.105–113 Hence, the role of SH on longevity and ND remain elusive. The goal of this project is to analyze the association between sex hormones and epigenetic aging and age- related neurodegenerative diseases. The project is divided into three aims. In the first aim, three different methods to predict SH levels will be created using whole genome genetics, large-scale methylation data, and questionnaire-based information. In the second aim, both measured SH and SH predictive scores will be associated with epigenetic age. Epigenetic age is known to be strongly associated with mortality and therefore, is a robust measure to estimate longevity.114,115 In the third aim, the development of ND (Alzheimer’s disease and Parkinson’s disease), as well as age of onset (Alzheimer’s disease, Parkinson’s disease and Huntington’s disease), will be associated with the SH predictive scores based on the first aim. Finally, assuming an association was identified in aims 2 and 3, mediation analysis will be performed as a potential sub-aim to analyze whether epigenetic aging can partially explain the association between sex hormones and ND. To ensure statistical power and the ability to verify and replicate the findings, several large observational datasets will be used. These studies and approaches will address the role of sex hormones from various angles, and will help to triangulate evidence and inform future research into potential therapeutic targets. With training from, and collaborations with several experts in genetic, epigenetic, and epidemiological analyses, the applicant will gain expertise to unlock some of these questions and contribute to aging and neurodegenerative disease-related discoveries. Maximizing an interdisciplinary approach, incorporating genetics, epigenetics, epidemiology, biostatistics and neurology considerations, will generate a broad range of independent research.

抽象的 随着一般人口的年龄，了解导致寿命，健康衰老和的因素 残疾至关重要。性激素（SH）已被认为是造成的原因之一 寿命和神经退行性疾病的性别差异（ND）。13SH，特别是雌激素， 孕酮和睾丸激素）在动物和细胞线研究中显示了神经保护作用，14-16和 阿尔茨海默氏病与疾病有关的动物模型，17-24帕金森氏病，25-29和亨廷顿 疾病30–35先前的研究分析性激素的作用（生殖史或激素） ND的代谢基因）在人类观察研究中的寿命尚无定论。 36–104也是如此 不一致的是分析绝经后激素治疗的临床试验 因此，对ND.105–113的积极作用，因此SH在寿命和ND上的作用仍然难以捉摸。 该项目的目的是分析性激素与表观遗传衰老与年龄之间的关联 相关的神经退行性疾病。该项目分为三个目标。在第一个目标中，三个不同 预测SH水平的方法将使用整个基因组遗传学，大规模甲基化数据和 基于问卷的信息。在第二个目标中，测得的SH和SH预测分数都是 与表观遗传时代有关。已知表观遗传年龄与死亡率密切相关，因此 是估计寿命的强大措施。114,115在第三个目标中，ND的发展（阿尔茨海默氏病 和帕金森氏病）以及发病时代（阿尔茨海默氏病，帕金森氏病和亨廷顿的 疾病），将根据第一个目标与SH预测分数有关。最后，假设一个 在AIM 2和3中确定了关联，将进行调解分析作为潜在的子AIM 分析表观遗传衰老是否可以部分解释性激素与ND之间的关联。到 确保统计能力和验证和复制发现的能力，几个大观测数据集 将使用。这些研究和方法将从各个角度解决性激素的作用，并 将有助于对证据进行三角剖分，并为潜在的治疗靶标提供未来的研究。 通过与遗传，表观遗传学和流行病学专家的培训以及合作 分析，申请人将获得专业知识来解锁其中一些问题，并有助于衰老和 神经退行性疾病相关的发现。最大化跨学科的方法 遗传学，表观遗传学，流行病学，生物统计学和神经病学考虑因素，将产生广泛的范围 独立研究。