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

• 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
• 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' 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

 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：这是一个培训补助金，将给我的资源，发展成为一个学术物理学家，科学家。我的长期目标是研究阿尔茨海默病（AD）和大脑老化的神经退行性疾病，并将其与我作为神经病理学家的临床角色相结合（至少75%的时间用于研究）。这项赠款包括科学建议部分和培训部分。科学建议部分将提出三个问题。首先，我将询问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”）之间的基因甲基化是否存在差异。AD患者已被证明具有DNA甲基化的异常，并且β-淀粉样蛋白也已被证明引起DNA甲基化的改变。然而，“病理对照”具有升高的β-淀粉样蛋白水平，但没有痴呆。由于病理对照具有升高的β-淀粉样蛋白水平，并且β-淀粉样蛋白已显示引起改变的DNA甲基化，因此病理对照可能具有通常与AD相关的一些DNA甲基化异常，其不直接引起痴呆。通过比较AD脑组织和病理对照组织，我希望梳理出与痴呆症存在最密切相关的基因甲基化变化。其次，我将询问是否有DNA甲基化的变化，是预测恶化的认知状态在AD病理设置，使用患者人群，正在分流脑积水。最后，我将探讨 学习相关的DNA甲基化变化在AD小鼠模型中受损，其近似于在人类AD患者中观察到的一些甲基化异常。总之，这些实验将有助于梳理出异常DNA甲基化与AD认知受损的关联。我的博士论文是在计算神经科学实验室（即“干实验室”工作）。在我接受临床培训后的几年里，我已经精通了实验神经科学（即“湿实验室”工作）。这项培训补助金将利用这一背景，并训练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。我将在此期间完成三个培训目标：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，3）加深我对衰老和神经退行性变的认知后遗症的了解。总之，通过科学建议和培训计划，这项培训资助将为我提供资源，使我能够作为一名科学家蓬勃发展，并为阿尔茨海默病研究做出贡献。