A systems approach to DNA methylation, gene expression, and cognitive dysfunction in Alzheimer's disease

阿尔茨海默病 DNA 甲基化、基因表达和认知功能障碍的系统方法

基本信息

批准号：
8869425
负责人：
Andrew Franklin Teich
金额：
$ 12.69万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8869425
关键词：
APP-PS1 Aberrant DNA Methylation Affect Aging Alzheimer&apos s Disease Amyloid Autophagocytosis Autopsy Biology of Aging Biopsy Brain Cells Clinical Cognitive Collaborations Computational Technique Computer Analysis DNA Methylation Data Databases Dementia Doctor of Philosophy Drainage procedure Epigenetic Process Freezing Gene Expression Genes Genetic Transcription Genome Genomics Goals Grant Histologic Human Hydrocephalus Impaired cognition Knowledge Learning Link Memory Methods Methylation Modeling Modification Molecular Molecular Biology Mus Nature Nerve Degeneration Neurodegenerative Disorders Neurosciences Normal Pressure Hydrocephalus Operative Surgical Procedures Pathogenesis Pathologic Pathology Patients Physicians Physiological Processes Physiology Play Principal Investigator Research Resources Role Sampling Scientist Shunt Device Specificity Synapses System Techniques Testing Time Tissues Training Work aging brain base brain tissue cell type cognitive change computational neuroscience follow-up mouse model neuropsychological neurosurgery patient population prevent programs public health relevance research study skills social stigma transcriptome sequencing

项目摘要

DESCRIPTION: This is a training grant that will give me the resources to develop into an academic physician-scientist. My long- term goal is to do research that focuses on Alzheimer's disease (AD) and neurodegenerative diseases of the aging brain, and integrate this with my clinical role as a neuropathologist (with at least 75% of my time dedicated to research). This grant has a scientific proposal component as well as a training component. The scientific proposal component will ask three questions. First, I will ask if there are differences in gene methylation between AD patients and cognitively normal patients with a similar cortical ß-amyloid load ("pathological controls"). AD patients have been shown to have abnormalities in DNA methylation, and ß- amyloid has also been shown to cause alterations in DNA methylation. However, "pathologic controls" have elevated ß-amyloid levels but are not demented. Since pathologic controls have elevated ß-amyloid levels, and ß-amyloid has been shown to cause altered DNA methylation, pathologic controls may have some DNA methylation abnormalities normally associated with AD that do not directly cause dementia. By comparing AD brain tissue to pathological control tissue, I hope to tease out changes in gene methylation that correlate strongest with the presence of dementia. Second, I will ask whether there are changes in DNA methylation that are predictive of worsening cognitive status in the setting of AD pathology, using a patient population that is being shunted for hydrocephalus. Finally, I will explore whether learning-related changes in DNA methylation are impaired in a mouse model of AD that approximates some of the methylation abnormalities seen in human AD patients. In all, these experiments will help to tease out the association of abnormal DNA methylation with impaired cognition in AD. My PhD thesis was in a computational neuroscience lab (i.e. "dry-lab" work). I have spent the last several years after my clinical training becoming proficient in experimental neuroscience (i.e. "wet-lab" work). This training grant will take advantage of this background and train me in computational techniques of analyzing genomic and genome expression data, with a focus on applying these techniques to neurodegeneration and the aging brain. I will accomplish three training goals during the course of this grant; 1) Acquire the skills to perform computational analysis of genomic and genome expression data, 2) Deepen my knowledge of the molecular biology of aging, and 3) Deepen my knowledge of the cognitive sequelae of aging and neurodegeneration. In summary, this training grant, through the scientific proposal and the training plan, will give me the resources to flourish as a scientist and make a contribution to Alzheimer's disease research.

描述：这是一笔培训补助金，将为我提供发展成为一名学术医师科学家的资源。我的长期目标是开展专注于阿尔茨海默病 (AD) 和衰老大脑神经退行性疾病的研究，并将其整合起来。作为一名神经病理学家，我的临床角色（至少 75% 的时间用于研究）。这笔拨款包含科学提案部分和培训部分。首先，我会问是否。有差异AD 患者和具有相似皮质 β-淀粉样蛋白负荷的认知正常患者（“病理对照”）之间的基因甲基化存在差异，AD 患者已被证明 DNA 甲基化异常，并且 β-淀粉样蛋白也被证明会导致 DNA 改变。然而，“病理对照”的 β-淀粉样蛋白水平升高，但并未痴呆，因为病理对照的 β-淀粉样蛋白水平升高，并且 β-淀粉样蛋白水平升高。已被证明会导致 DNA 甲基化改变，病理对照可能具有一些通常与 AD 相关的 DNA 甲基化异常，但不会直接导致痴呆。通过将 AD 脑组织与病理对照组织进行比较，我希望能够找出相关性最强的基因甲基化变化。其次，我将使用因脑积水而被分流的患者群体来询问 DNA 甲基化的变化是否预示着 AD 病理学中认知状态的恶化。 AD 小鼠模型中与学习相关的 DNA 甲基化变化受到损害，这种变化与人类 AD 患者中观察到的一些甲基化异常相似。总而言之，这些实验将有助于弄清楚异常 DNA 甲基化与 AD 认知受损之间的关系。我的博士论文是在计算神经科学实验室（即“干实验室”工作）中进行的，在我接受临床培训后，我已经精通实验神经科学（即“湿实验室”工作）。培训补助金将利用这一背景，培训我分析基因组和基因组表达数据的计算技术，重点是将这些技术应用于神经退行性变和大脑老化，我将在这笔补助金的过程中实现三个培训目标1； ) 获得对基因组和基因组表达数据进行计算分析的技能，2) 加深我对衰老分子生物学的了解，以及 3) 加深我对衰老和神经退行性疾病的认知后遗症的了解总之，这项培训资助通过。科学的建议和培训计划，将为我提供作为一名科学家蓬勃发展的资源，并为阿尔茨海默病研究做出贡献。