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 随着总体人口老龄化，了解有助于长寿、健康老龄化和健康老龄化的因素 性激素（SH）受阻是导致残疾的最重要原因之一。 长寿和神经退行性疾病 (ND) 方面的性别差异。13 SH，特别是雌激素， 黄体酮和睾酮）在动物和细胞系研究中已显示出神经保护作用，14-16 阿尔茨海默病、17-24 帕金森病、25-29 和亨廷顿舞蹈病的疾病相关动物模型 疾病。30–35 先前的研究分析了性激素的影响（生殖史或激素） 代谢基因）对 ND 和寿命的影响在人类观察研究中还没有定论 36-104。 分析绝经后激素治疗是否有效果的临床试验不一致 对 ND.105-113 的积极影响 因此，SH 对长寿和 ND 的作用仍然难以捉摸。 该项目的目标是分析性激素与表观遗传衰老和年龄之间的关联 该项目分为三个目标，第一个目标是三个不同的目标。 将利用全基因组遗传学、大规模甲基化数据和 在第二个目标中，测量的 SH 和 SH 预测分数将是基于问卷的信息。 已知表观遗传年龄与死亡率密切相关，因此， 是估计寿命的强有力的衡量标准。114,115 在第三个目标中，ND（阿尔茨海默病）的发展 和帕金森病），以及发病年龄（阿尔茨海默病、帕金森病和亨廷顿舞蹈病） 疾病），将与基于第一个目标的 SH 预测分数相关联。 关联性已在目标 2 和 3 中确定，中介分析将作为潜在的子目标进行 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。 确保统计能力以及验证和复制研究结果的能力，几个大型观测数据集 这些研究和方法将从不同角度探讨性激素的作用，以及 将有助于对证据进行三角测量，并为未来潜在治疗目标的研究提供信息。 经过遗传、表观遗传和流行病学领域多位专家的培训和合作 分析后，申请人将获得专业知识来解决其中一些问题，并有助于老龄化和 最大限度地利用跨学科方法，结合神经退行性疾病相关的发现。 遗传学、表观遗传学、流行病学、生物统计学和神经学方面的考虑，将产生广泛的 独立研究。