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：这是一项培训补助金，它将为我提供发展为学术身体科学家的资源。我的长期目标是进行研究的研究，重点是老年大脑的阿尔茨海默氏病（AD）和神经退行性疾病，并将其与我作为神经病理学家的临床作用相结合（我至少有75％的时间致力于研究）。该赠款具有科学提案部分以及培训组成部分。科学提案部分将提出三个问题。首先，我会问AD患者与认知正常患者之间的基因甲基化差异是否存在差异，具有相似的皮质β-淀粉样蛋白负荷（“ patiological Controls”）。已显示AD患者在DNA甲基化中具有异常，并且ß-淀粉样蛋白也已被证明会导致DNA甲基化的改变。然而，“病理控制”的β-淀粉样蛋白水平升高，但没有痴呆。由于病理控制升高，β-淀粉样蛋白水平升高，并且已证明β-淀粉样蛋白会导致DNA甲基化改变，因此病理控制可能与通常不会直接引起痴呆的AD相关的DNA甲基化异常。通过将AD脑组织与病理控制组织进行比较，我希望取消与痴呆症的存在相关的基因甲基化的变化。其次，我将使用正在为脑积水的患者群体进行的患者群体来预测DNA甲基化的变化可以预测AD病理学的认知状况。最后，我将探索是否在AD的小鼠模型中，与学习相关的DNA甲基化变化受损，该模型近似于人类AD患者中某些甲基化异常。总的来说，这些实验将有助于教授异常DNA甲基化与AD认知受损的关联。我的博士学位论文是在计算神经科学实验室（即“干lab”工作）中的。在我的临床训练变得精通实验性神经科学（即“湿lab”工作）之后，我已经度过了几年。该培训赠款将利用这种背景，并在分析基因组和基因组表达数据的计算技术中训练我，重点是将这些技术应用于神经变性和衰老大脑。在这笔赠款过程中，我将实现三个培训目标； 1）获取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变性的认知后遗症的了解。总而言之，通过科学建议和培训计划，这项培训赠款将为我提供作为科学家蓬勃发展的资源，并为阿尔茨海默氏病研究做出贡献。