Exploring Common Biological Pathways Underlying Insulin Resistance and Alzheimer Disease using Genetic and Omic Tools

使用遗传和组学工具探索胰岛素抵抗和阿尔茨海默病的常见生物途径

• 批准号: 10373944
• 负责人: Chloé Sarnowski
• 金额: $ 8.94万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2022-08-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373944
• 关键词: Address; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Apoptosis; Bioinformatics; Biological; Biological Markers; Biology; Blood; Blood - brain barrier anatomy; Brain; Brain region; Bypass; Cognition; Collaborations; Complex; DNA Methylation; Data; Dementia; Doctor of Philosophy; Elderly; Environmental Risk Factor; Evaluation; Failure; Framingham Heart Study; Functional disorder; Gene Expression; Genes; Genetic; Genetic Annotation; Genetic Risk; Genetic study; Genomics; Glucose; Goals; Grant; Impaired cognition; Individual; Insulin; Insulin Resistance; Joints; Knowledge; Late Onset Alzheimer Disease; Lead; Learning; Machine Learning; Measures; Memory; Mendelian randomization; Mentorship; Methods; Mission; Molecular Profiling; Nerve Degeneration; Neurofibrillary Tangles; Obesity; Outcome; Pathogenesis; Pathway interactions; Patients; Phase; Plasma; Predisposition; Prevalence; Principal Investigator; Public Health; Research; Research Personnel; Research Project Grants; Risk Factors; Role; Scientist; Senile Plaques; Statistical Methods; Techniques; Testing; Therapeutic Intervention; Tissues; Training; Trans-Omics for Precision Medicine; United States National Institutes of Health; base; brain cell; brain health; brain tissue; career; career development; design; endophenotype; experience; genetic resistance; genetic risk factor; genetic variant; genomic locus; human disease; improved; innovation; insight; instrument; insulin sensitivity; mild cognitive impairment; multiple omics; neuroimaging; novel; peripheral blood; prevent; preventive intervention; programs; religious order study; tau Proteins; tissue resource; tool; trait; transcriptome sequencing; treatment response; vascular risk factor; whole genome

Project Summary / Abstract Insulin resistance (IR) is a major risk factor for Alzheimer’s disease (AD) but the mechanisms by which IR predisposes to AD is unknown, notably, if IR is causally related to AD and which regulatory mechanisms underlie IR and contribute to AD. The proposal is designed to address these critical gaps in scientific knowledge by using omics to evaluate the causal relationship of IR on AD and to reveal new regulatory mechanisms involved in IR and AD. The Principal Investigator (PI), Dr. Sarnowski, is a statistical geneticist and an early career investigator with a research focus on the identification of genetic and environmental risk factors of complex traits. The long-term goal of this project is to identify individuals who will benefit from treatments improving insulin sensitivity to better prevent, delay or stop the progression of AD. The overall objective is to better characterize mechanisms by which IR contributes to AD and evaluate how they may differ from known mechanisms involved in AD pathogenesis. The central hypothesis is that omics will help to better understand and characterize the relationships between IR and AD. The rationale is that omics will help to disentangle the mode of action of IR on AD and identify targets for preventive and therapeutic interventions. Guided by strong preliminary results in the Framingham Heart Study, the hypothesis will be tested through three specific aims: 1) Determine if IR is causally related to AD in a Mendelian Randomization (MR) framework with various genetic instrument variables (IVs); 2) Characterize molecular signatures of IR associated with AD using brain and blood omic data; and 3) Develop a joint test to evaluate the genetic contribution at IR signatures associated with AD. In Aim 1, genetic IVs, including standard and pathway-specific genetic risk scores and predictors identified by machine learning, will be constructed to evaluate the causal relationships between IR and AD using various MR methods. In Aim 2, association analyses will be performed to identify brain and blood omic signatures of IR related to AD. In Aim 3, new integrative statistical methods leveraging annotations will be developed to evaluate the genetic contribution on omics at loci involved in IR and AD. Career development activities will include training in AD pathophysiology, multi-omic analysis and machine learning techniques through coursework, seminars, mentorship, and collaborations with a team of leading expert scientists. The approach is innovative by shifting focus to omics to study the regulatory mechanisms involved in IR and AD. The proposed research is significant as the expected outcomes will contribute to a better understanding of how insulin sensitivity can be improved to better prevent, delay or stop the progression of AD, reduce cognitive decline and prevalence of dementia due to AD, and promote brain health in late life. The experience acquired in achieving the aims of this grant will advance the PI’s career to an independent statistical geneticist with bioinformatics expertise, to dissect how vascular risk factors interact with genomics to influence AD and dementia susceptibility using large-scale omics.

项目摘要/摘要 胰岛素抵抗(IR)是阿尔茨海默病(AD)的主要危险因素，但IR的机制 阿尔茨海默病的易感性尚不清楚，特别是IR是否与AD有因果关系，以及哪些调节机制 为IR奠定基础，并为AD做出贡献。该提案旨在解决科学研究领域的这些关键空白。 运用组学知识评价IR与AD的因果关系并揭示新的调控机制 IR和AD的发病机制。首席调查员(PI)萨诺斯基博士是一名统计遗传学家， 早期职业调查员，研究重点是识别遗传和环境风险因素 具有复杂的特征。该项目的长期目标是确定哪些人将从治疗中受益 改善胰岛素敏感性，更好地预防、延缓或阻止AD的进展。总体目标是 更好地描述IR导致AD的机制，并评估它们与已知的机制有何不同 阿尔茨海默病发病机制。核心假设是，组学将有助于更好地理解 并对IR与AD之间的关系进行了表征。其基本原理是，经济学将有助于理清 IR对AD的作用模式，并确定预防和治疗干预的目标。以Strong为指导 在弗雷明翰心脏研究的初步结果中，这一假设将通过三个具体目标进行检验：1) 在具有不同基因的孟德尔随机化(MR)框架中确定IR是否与AD有因果关系 仪器变量(IV)；2)使用脑和血液表征与AD相关的IR的分子特征 基因组数据；以及3)开发一种联合测试，以评估与AD相关的IR签名的遗传贡献。 在目标1中，遗传IVs，包括标准的和特定于路径的遗传风险分数和预测因子，由 将构建机器学习，以使用各种MR来评估IR和AD之间的因果关系 方法：研究方法。在目标2中，将执行关联分析以识别IR的脑和血液组学特征 与AD有关。在目标3中，将开发利用注释的新的综合统计方法来评估 IR和AD相关基因座的遗传贡献。职业发展活动将包括培训 在AD病理生理学、多组体分析和机器学习技术方面，通过课程、研讨会、 指导，以及与领先的专家科学家团队的合作。这种方法是创新的，通过改变 关注组学，研究IR和AD的调控机制。这项拟议的研究具有重要意义 因为预期的结果将有助于更好地理解如何改善胰岛素敏感性 更好地预防、延缓或阻止AD的进展，减少因以下原因而导致的认知衰退和痴呆症患病率 广告，并促进晚年的大脑健康。在实现这笔赠款的目标方面所获得的经验将有所进步。 PI的职业生涯是一名拥有生物信息学专业知识的独立统计遗传学家，分析血管风险 因素与基因组学相互作用，通过大规模组学影响AD和痴呆症的易感性。