The Role of Genetic Variation in Alzheimer's Disease

遗传变异在阿尔茨海默病中的作用

• 批准号: 8516926
• 负责人: Robyn A Honea
• 金额: $ 12.53万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8516926
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Animal Model; Apolipoprotein E; Atrophic; Behavioral; Behavioral Genetics; Biological; Biological Models; Brain; Brain Diseases; Brain imaging; Brain-Derived Neurotrophic Factor; Burn injury; Candidate Disease Gene; Clinical; Clinical Research; Cognition; Cognitive; Cognitive deficits; Collaborations; Complex; Data; Data Analyses; Data Set; Development; Disease; Disease Progression; Doctor of Philosophy; Education; Elderly; Environment; Environmental Risk Factor; Exercise; Exercise Physiology; Experimental Designs; Foundations; Functional Magnetic Resonance Imaging; Funding; Future; Genes; Genetic; Genetic Research; Genetic Variation; Goals; Growth; Health; Hippocampus (Brain); Human; Image; Image Analysis; Impaired cognition; Individual; Investigation; K-Series Research Career Programs; Kansas; Laboratories; Lead; Learning; Magnetic Resonance Imaging; Marriage; Measures; Medical center; Memory; Mentors; Mentorship; Methodology; Molecular; Molecular Genetics; National Institute of Mental Health; Nerve Degeneration; Neurology; Pathology; Phenotype; Physical activity; Physiology; Population; Prevalence; Process; Psychotic Disorders; Research; Role; Schizophrenia; Series; Single Nucleotide Polymorphism; Stress; Structure; Testing; Training; Universities; Variant; Washington; Work; aging brain; base; brain volume; career; cerebral atrophy; design; disease phenotype; endophenotype; experience; fitness; gene environment interaction; genetic variant; hippocampal atrophy; interest; neuroimaging; programs; relating to nervous system; translational study

DESCRIPTION (provided by applicant): This K award will be integral in the development of Dr. Honea's career plan, which was designed to extend her neuroimaging investigations schizophrenia, to studying complex genetic and environmental interactions and their impact on imaging markers of neurodegeneration in Alzheimer's disease. While Dr. Honea has successfully applied VBM methodologies to ask initial questions about AD risk, she needs more advanced training in Alzheimer's disease clinical methodology, genetics, and methodology in exercise physiology and fitness. Dr. Honea will work in the department of Neurology at the University of Kansas Medical Center (KUMC) under mentorship of Dr. Jeffrey Burns to learn Alzheimer's disease clinical methodology. Dr. Honea will capitalize on several of the University of Kansas' research strengths: the Hoglund Brain Imaging Center, Genetics Research in the Molecular and Integrative Physiology Department, the General Clinical Research Center, and the Alzheimer's and Memory Program. The proposed additional training will allow her to effectively study the role of genetic variation in Alzheimer's disease in large datasets, such as the ADNI and Washington University ADRC datasets, and then apply those results to the study of gene x environment interactions. In order to ask more complex questions about the role of genetic variation in Alzheimer's Disease neurodegeneration, she will need to develop new collaborations with AD genetics expert Alison Goate, PhD. Additional mentored training in genetics under Dr. Goate will give her the ability to investigate complex interactions with other genes, and environmental moderators of stress and protection relevant to aging research. Training in imaging genetics will be provided by Dr. Daniel Weinberger, Chief of the Clinical Brain Disorders Branch and Director of the Genes, Cognition, and Psychosis program at NIMH. Additional technical training will be provided by Cary Savage, PhD in fMRI experimental design, analysis, and the application of fMRI to Alzheimer's populations. The combination of well-funded and experienced mentors, education, laboratory training, and clinical experience provides an ideal vehicle for advancing Dr. Honea's career goals. Dr. Honea's overall goal is to conduct a series of imaging analyses to begin examining genetic variation and the influence of this variation on brain structure and function, and its relationship to CR fitness. As a model system to begin examining gene by environment interactions, we have identified several candidate genes associated with AD risk (BDNF, APOE, CLU, PICALM, CR1, TOMM40) 21, 22, and will take them through a three-step process. Our overall hypothesis is that CR fitness may moderate the neurodegenerative effect of genetic variation in one or more genes on MRI phenotypes of AD progression. Aim 1: Gene - Brain Structure: Assess the relationship of selected candidate genes with MRI phenotypes and cognitive markers of AD progression. We will first use ADNI data to characterize the relationship between each single nucleotide polymorphism (SNP) and baseline regional brain volume, rates of hippocampal and whole brain atrophy, and change in ADAS-COG in all subject groups (ND, MCI, and AD) for maximum power. We will then replicate all tests in the longitudinal Washington University ADRC dataset. These secondary data analyses in two well-characterized datasets will allow us to verify pertinent gene to brain structure relationships. Aim 2: Gene x Environment - Brain Structure: Examine whether CR fitness moderates the relationship between genetic variation and brain neurodegeneration. We have demonstrated that increased levels of CR fitness may protect brain volume in early AD 51, 52, although the mechanism for this is unknown. The beneficial effects of CR fitness may moderate the relationship between genetic variation and neurodegeneration53-57. We will test whether CR fitness moderates the relationship between candidate SNPs related to brain structure, and hippocampal and whole brain atrophy in a longitudinal dataset. Aim 3: Gene x Environment - Brain Function: Examine the influence of genetic variation on the relationship of CR Fitness with fMRI markers of neural activity. CR fitness 30, 51, 52and genetic variation58, 59 have independently been shown to moderate neural activity during learning and memory, although their interaction is unexplored. We will use fMRI to measure the impact of fitness on hippocampal learning and memory, and characterize whether key genes associated with hippocampal structure and function moderate this relationship. The proposed research will first characterize genetic mechanisms influencing hippocampal structure and function, then test for gene-environment interactions that might moderate brain neurodegeneration. While the initial focus is on genes such as APOE, based on its relationship to the MRI endophenotypes of AD, and BDNF based on its involvement in exercise-related brain changes,60, 61 these analyses will provide a strategy and foundation from which to advance Dr. Honea's independent research on gene by environment interactions relevant for brain health. The marriage of molecular genetics with environmental factors will provide a fertile direction for translational aging research and a step towards identifying future therapies for AD62.

描述（由申请人提供）：该 K 奖将成为 Honea 博士职业计划发展的一部分，该计划旨在扩展她对精神分裂症的神经影像学研究，以研究复杂的遗传和环境相互作用及其对阿尔茨海默氏症神经退行性疾病影像标记物的影响疾病。虽然 Honea 博士已成功应用 VBM 方法来提出有关 AD 风险的初步问题，但她需要在阿尔茨海默病临床方法、遗传学以及运动生理学和健身方法方面接受更高级的培训。 Honea 博士将在 Jeffrey Burns 博士的指导下在堪萨斯大学医学中心 (KUMC) 神经科工作，学习阿尔茨海默病临床方法。 Honea 博士将利用堪萨斯大学的多项研究优势：霍格伦德脑成像中心、分子和综合生理学系的遗传学研究、普通临床研究中心以及阿尔茨海默病和记忆项目。拟议的额外培训将使她能够在大型数据集中（例如 ADNI 和华盛顿大学 ADRC 数据集）有效研究遗传变异在阿尔茨海默病中的作用，然后将这些结果应用于基因 x 环境相互作用的研究。为了提出有关遗传变异在阿尔茨海默氏病神经变性中的作用的更复杂的问题，她需要与阿尔茨海默病遗传学专家艾莉森·戈特博士开展新的合作。 Goate 博士在遗传学方面的额外指导培训将使她能够研究与其他基因的复杂相互作用，以及与衰老研究相关的压力和保护的环境调节因素。影像遗传学培训将由 NIMH 临床脑部疾病部门负责人兼基因、认知和精神病项目主任 Daniel Weinberger 博士提供。 Cary Savage 博士将在 fMRI 实验设计、分析以及 fMRI 在阿尔茨海默病人群中的应用方面提供额外的技术培训。资金雄厚、经验丰富的导师、教育、实验室培训和临床经验相结合，为推进 Honea 博士的职业目标提供了理想的工具。 Honea 博士的总体目标是进行一系列成像分析，以开始检查遗传变异以及这种变异对大脑结构和功能的影响，及其与 CR 适应性的关系。作为开始通过环境相互作用检查基因的模型系统，我们已经确定了几个与 AD 风险相关的候选基因（BDNF、APOE、CLU、PICALM、CR1、TOMM40）21、22，并将引导它们完成一个三步过程。我们的总体假设是，CR 适应性可能会减轻一个或多个基因的遗传变异对 AD 进展的 MRI 表型的神经退行性影响。目标 1：基因 - 大脑结构：评估所选候选基因与 MRI 表型和 AD 进展认知标记的关系。我们将首先使用 ADNI 数据来表征所有受试者组（ND、MCI 和 AD）中每个单核苷酸多态性 (SNP) 与基线区域脑容量、海马和全脑萎缩率以及 ADAS-COG 变化之间的关系以获得最大功率。然后，我们将复制华盛顿大学 ADRC 纵向数据集中的所有测试。对两个特征明确的数据集中的二次数据分析将使我们能够验证相关基因与大脑结构的关系。目标 2：基因 x 环境 - 大脑结构：检查 CR 适应性是否调节遗传变异与大脑神经退行性变之间的关系。我们已经证明，提高 CR 适应性水平可能会保护公元 51、52 ​​早期的脑容量，尽管其机制尚不清楚。 CR 健身的有益作用可能会调节遗传变异与神经退行性变之间的关系53-57。我们将在纵向数据集中测试 CR 适应性是否调节与大脑结构相关的候选 SNP 与海马和全脑萎缩之间的关系。目标 3：基因 x 环境 - 大脑功能：检查遗传变异对 CR 健康度与神经活动 fMRI 标记之间关系的影响。 CR 适应性 30、51、52 ​​和遗传变异 58、59 已被独立证明可以调节学习和记忆过程中的神经活动，尽管它们的相互作用尚未被探索。我们将使用功能磁共振成像来测量健身对海马学习和记忆的影响，并表征与海马结构和功能相关的关键基因是否调节这种关系。拟议的研究将首先描述影响海马结构和功能的遗传机制，然后测试可能缓解大脑神经退行性变的基因与环境的相互作用。虽然最初的重点是 APOE 等基因（基于其与 AD MRI 内表型的关系），以及 BDNF（基于其参与运动相关的大脑变化）60、61，但这些分析将为推进提供策略和基础。 Honea 博士对与大脑健康相关的环境相互作用的基因进行了独立研究。分子遗传学与环境因素的结合将为转化衰老研究提供丰富的方向，并朝着确定 AD62 的未来疗法迈出一步。