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: 8706740
• 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/8706740
• 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奖将是HONEA博士的职业计划的制定，该计划旨在扩大她的神经影像学调查精神分裂症，以研究复杂的遗传和环境相互作用及其对阿尔茨海默氏病神经变性的成像标记的影响。尽管Honea博士成功地应用了VBM方法来提出有关AD风险的最初问题，但她需要在阿尔茨海默氏病临床方法，遗传学和运动生理学和健身方面进行更高级的培训。 Honea博士将在堪萨斯大学医学中心（KUMC）的神经病学系的指导下在杰弗里·伯恩斯（Jeffrey Burns）的指导下工作，以学习阿尔茨海默氏病临床方法论。 Honea博士将利用堪萨斯大学的几个研究优势：Hoglund脑成像中心，分子和综合生理学系的遗传学研究，一般临床研究中心以及阿尔茨海默氏症和记忆计划。提出的额外培训将使她能够有效研究大型数据集中遗传变异在阿尔茨海默氏病中的作用，例如ADNI和华盛顿大学ADRC数据集，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多复杂问题，她将需要与AD遗传学专家Alison Goate（博士）开发新的合作。 Goate博士在遗传学下进行的其他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环境主持人。 NIMH临床脑部疾病分支的负责人兼基因，认知和精神病计划主任丹尼尔·温伯格（Daniel Weinberger）博士将提供成像遗传学的培训。 fMRI实验设计，分析以及fMRI在阿尔茨海默氏症人群中的应用中，Cary Savage，博士学位将提供其他技术培训。资金丰富和经验丰富的导师，教育，实验室培训和临床经验的结合为促进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，以开始研究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，我们已经确定了与AD风险相关的几个候选基因（BDNF，APOE，CLU，PICALM，PICALM，CR1，TOMM40）21、22，并将通过三步过程将它们带走。我们的总体假设是，CR适应性可能适应一个或多个基因对AD进展的MRI表型中遗传变异的神经退行性作用。目标1：基因 - 大脑结构：评估选定候选基因与MRI表型和AD进展的认知标记的关系。我们将首先使用ADNI数据来表征每个单个核苷酸多态性（SNP）和基线区域大脑体积，海马和整个脑萎缩的速率以及所有受试者组（ND，MCI和AD）的ADAS-COG的变化，以获得最大的功率。然后，我们将在华盛顿大学ADRC数据集中复制所有测试。这些辅助数据分析在两个特征良好的数据集中将使我们能够验证与大脑结构关系相关的基因。 AIM 2：基因X环境 - 大脑结构：检查CR适应性是否会节省遗传变异与脑神经退行性之间的关系。我们已经证明，CR健身水平的提高可以保护公元51，52早期的大脑体积，尽管其机制尚不清楚。 CR适应性的有益作用可能适应遗传变异与神经变性之间的关系53-57。我们将测试CR适应性是否会节省与大脑结构相关的候选SNP之间的关系，以及纵向数据集中的海马和整个脑萎缩。目标3：基因X环境 - 大脑功能：检查遗传变异对CR适应性与神经活动的fMRI标志的影响。 CR Fitness 30、51、52和遗传变异58、59在学习和记忆过程中已独立地显示了中度的神经活动，尽管它们的相互作用尚未探索。我们将使用fMRI来衡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适度这种关系。拟议的研究将首先表征影响海马结构和功能的遗传机制，然后测试可能中度大脑神经变性的基因环境相互作用。虽然最初的重点是基于APOE等基因，但基于其与AD的MRI内表型的关系，而BDNF基于其参与与运动相关的大脑变化的参与，但61、61这些分析将提供一种策略和基础，从而从与大脑健康相关的环境相互作用来推动Honea博士对基因的独立研究。分子遗传学与环境因素的结婚将为转化衰老研究提供肥沃的方向，并迈向确定AD62未来疗法的一步。