Sex Differences in Alzheimer's disease-Related Pathology: Role of Mitochondrial Function and Metabolic Health

阿尔茨海默病相关病理学的性别差异：线粒体功能和代谢健康的作用

基本信息

批准号：
10643340
负责人：
Kyoko Konishi
金额：
$ 12.85万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10643340
关键词：
8-hydroxy-2&apos -deoxyguanosine Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amyloid beta-42 Anterior Area Bioenergetics Biological Markers Biometry Blood specimen Brain Brain Diseases Brain imaging Cardiometabolic Disease Cell Respiration Cells Cerebrum Chronology Data Data Analyses Data Collection Estradiol Family Study Frequencies Functional Magnetic Resonance Imaging Functional disorder Genetic Glucose Goals Gonadal Steroid Hormones Grant Health Hippocampus Individual Inferior Insulin Knowledge Life Expectancy Light Link Lipids Measures Mediating Mediator Medical Memory Memory Loss Menopausal Status Menopause Mentored Research Scientist Development Award Metabolic Metabolic Diseases Metabolic dysfunction Mitochondria New England Organelles Oxidative Stress Parietal Lobe Pathology Pathway interactions Performance Perimenopause Peripheral Blood Mononuclear Cell Persons Physiological Play Positioning Attribute Postmenopause Prefrontal Cortex Premenopause Process Production Public Health Reproductive History Research Research Personnel Respiration Risk Factors Role Sex Differences Site Source Structure Testing Time Training Translational Research United States National Institutes of Health Woman Work Writing aged blood-based biomarker career cingulate cortex clinical diagnosis cohort follow-up glucose metabolism imaging modality in vivo knowledge base men middle age mitochondrial dysfunction neurofilament novel offspring precision medicine prenatal prospective reproductive senescence sex skills targeted treatment tau Proteins white matter

项目摘要

Project Summary/Abstract My career goal is to become a leading researcher in the field of sex differences in Alzheimer’s disease (AD), with a specific focus on metabolic mediators and mitochondrial function. To this end, my specific training goals in this K01 proposal include: 1) Increasing expertise and knowledge around sex differences in the brain, 2) Expanding my knowledge in metabolic and mitochondrial function in relation to AD and obtain training in biomarker research, and 3) Developing proficiency in translational research and biostatistics for data analysis. The NIA K01 Mentored Research Scientist Development Award will support my training and provide me with the knowledge base and skills needed to become an independent investigator. These training goals will be achieved in conjunction with the testing of my specific aims, which are built on promising preliminary data showing that metabolic health impacts memory circuitry function over the menopausal transition, potentially through mechanisms of oxidative stress. Two-thirds of patients with AD are women. Beyond life expectancy rates, there are sex-specific and sex-dependent genetic and physiologic factors that contribute to the higher frequency of AD in women. Midlife metabolic dysfunction, which significantly differs by sex, has long been recognized as a risk factor for AD. Despite this, the pathophysiology underlying this relationship remains largely unknown. I will test that hypothesis that mitochondrial function plays a critical role in understanding sex differences in memory circuitry function and the early emergence of AD-related pathology. Data will be leveraged from the unique New England Family Study (NEFS) prenatal cohort (N=212; 106M:106F), born between 1959-1966 and followed for >60 years. Detailed medical/reproductive histories, metabolic assessments, memory assessments, and stored blood samples were collected from offspring at ages 45-55 (T1 in R01MH090291). These same individuals are currently being assessed in an 8-year follow up, at ages 52-65 (T2 in R01AG067019), using the same T1 measures with additional brain imaging modalities. I have a unique window of opportunity to examine how mitochondrial function affects memory circuitry and AD-related pathology in a sex-dependent manner. Further, from T1 to T2, some women transitioned to menopause and thus I will be able to prospectively explore the longitudinal impact of reproductive aging, metabolic health, and mitochondrial function on memory decline and the accumulation of AD-related pathology. This proposal will examine mitochondrial function as a pathophysiological mechanism for sex differences in memory circuitry and risk for AD. Findings will have significant long-term implications for the co-occurrence of brain and metabolic disorders and highlight potential mechanistic targets for therapeutic strategies.

项目概要/摘要我的职业目标是成为阿尔茨海默病性别差异领域的领先研究员（AD），特别关注代谢介质和线粒体功能，为此，我进行了专门的训练。 K01 提案的目标包括：1）增加有关大脑性别差异的专业知识和知识， 2) 扩展我在与 AD 相关的代谢和线粒体功能方面的知识，并获得以下方面的培训生物标志物研究，以及 3) 提高转化研究和生物统计学数据分析的能力。 NIA K01 指导研究科学家发展奖将支持我的培训并为我提供这些培训目标将是成为独立调查员所需的知识基础和技能。结合我的具体目标的测试而实现，这些目标建立在有希望的初步数据的基础上表明代谢健康可能会影响更年期过渡期间的记忆回路功能通过氧化应激机制。三分之二的 AD 患者是女性，除了预期寿命之外，还存在性别差异和性别差异。性别依赖性遗传和生理因素导致女性中年 AD 发生率较高。代谢功能障碍因性别而存在显着差异，长期以来一直被认为是 AD 的危险因素。尽管如此，这种关系背后的病理生理学仍然很大程度上未知，我将对此进行测试。假设线粒体功能在理解记忆回路的性别差异中起着关键作用功能和 AD 相关病理学的早期出现将利用独特的新数据。英格兰家庭研究 (NEFS) 产前队列 (N=212; 106M:106F)，出生于 1959-1966 年间，并进行了随访 >60 年详细的医疗/生殖史、代谢评估、记忆评估并存储。从 45-55 岁的后代（R01MH090291 中的 T1）采集血液样本。目前正在进行为期 8 年的随访评估，年龄为 52-65 岁（R01AG067019 中的 T2），使用相同的 T1 我有一个独特的机会来检查如何使用额外的大脑成像方式。线粒体功能以性别依赖性方式影响记忆回路和 AD 相关病理。从 T1 到 T2，一些女性过渡到更年期，因此我将能够前瞻性地探索生殖衰老、代谢健康和线粒体功能对记忆衰退和记忆衰退的纵向影响该提案将检查线粒体功能作为 AD 相关病理的积累。记忆回路性别差异和 AD 风险的病理生理机制。对大脑和代谢紊乱同时发生具有重大的长期影响，并强调潜力治疗策略的机械目标。