An integrative analysis of DNA methylation, transcriptomic changes, and cognitive dysfunction in Alzheimer's disease

阿尔茨海默病 DNA 甲基化、转录组变化和认知功能障碍的综合分析

• 批准号: 9353721
• 负责人: Andrew Franklin Teich
• 金额: $ 21.09万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9353721
• 关键词: Aberrant DNA Methylation; Alzheimer' s Disease; Amyloid beta-Protein; Applications Grants; Autopsy; Binding; Bioinformatics; Biology of Aging; Biopsy; Brain; Cells; Clinical; Cognitive; Collaborations; Computational Technique; Computer Analysis; DNA; DNA Methylation; DNA analysis; Data; Dementia; Disease; Doctor of Philosophy; Drainage procedure; Epigenetic Process; Freezing; Future; Gene Expression; Genes; Genetic Transcription; Genome; Genomics; Goals; Grant; Histologic; Human; Hydrocephalus; Impaired cognition; Knowledge; Leadership; Link; Methodology; Methods; Methylation; Modification; Molecular; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neuropsychology; Neurosciences; New York; Normal Pressure Hydrocephalus; Pathogenesis; Pathologic; Pathology; Patients; Physicians; Play; Principal Investigator; Research; Resources; Role; Sampling; Scientist; Senile Plaques; Shunt Device; Specificity; Techniques; Time; Tissues; Training; Translating; Universities; Validation; Work; Writing; aging brain; brain tissue; cell type; cognitive change; computational neuroscience; demented; density; experimental study; follow-up; neurosurgery; patient population; prevent; programs; promoter; skills; tau Proteins; tool; transcription factor; transcriptomics

Program Director/Principal Investigator (Last, First, Middle): Teich, Andrew Franklin Project Summary: 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 two questions. First, I will ask if there are differences in gene methylation between AD patients and cognitively normal patients with a similar cortical β-amyloid load (“pathological controls”). AD patients have been shown to have abnormalities in DNA methylation, and β- amyloid has also been shown to cause alterations in DNA methylation. However, “pathologic controls” have elevated β-amyloid levels but are not demented. Since pathologic controls have elevated β-amyloid levels, and β-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. 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. In addition, this training grant is coinciding with my elevation to Co-Director of the New York Brain Bank at Columbia University. I will accomplish four training goals during the course of this grant; 1) Acquire a skill set to facilitate my new leadership role at Columbia, 2) Acquire the skills to perform computational analysis of genomic and genome expression data, 3) Deepen my knowledge of aging biology, 4) Acquire skills to succeed in writing my first R01 grant. 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. 0925-0001/0002 (Rev. 08/12) Page Continuation Format Page

项目负责人/主要研究者（最后，第一，中间）：Teich，Andrew富兰克林 项目摘要： 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- 长期目标是做研究，重点是阿尔茨海默病（AD）和神经退行性疾病的 老化的大脑，并将其与我作为神经病理学家的临床角色相结合（至少有75%的时间 致力于研究）。这项赠款包括科学建议部分和培训部分。的 科学建议部分将提出两个问题。首先，我会问是否有基因差异， 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之间的甲基化 （“病理对照”）。AD患者已被证明存在DNA甲基化异常，并且β- 淀粉样蛋白还显示引起DNA甲基化的改变。然而，“病理对照”具有 β-淀粉样蛋白水平升高，但没有痴呆。由于病理对照具有升高的β-淀粉样蛋白水平， β-淀粉样蛋白已被证明会导致DNA甲基化改变，病理对照可能有一些DNA甲基化改变。 通常与AD相关的甲基化异常并不直接导致痴呆。通过比较AD 脑组织与病理对照组织，我希望梳理出基因甲基化的变化， 最强的是痴呆症。其次，我会问是否有DNA甲基化的变化， 预测AD病理学背景下认知状态恶化，使用的患者人群 因为脑积水被分流总之，这些实验将有助于梳理出异常的 DNA甲基化与AD患者认知功能受损我的博士论文是在一个计算神经科学实验室（即。 “干实验室”工作）。在我的临床训练之后，我花了几年的时间来精通实验。 神经科学（即“湿实验室”工作）。这个培训补助金将利用这一背景，并培养我在 分析基因组和基因组表达数据的计算技术，重点是应用这些 神经退化和大脑老化的技术。另外，这份培训补助金正好与我的 晋升为哥伦比亚大学纽约脑库的联合主任。我将完成四项训练 在此期间的目标补助金; 1）获得一套技能，以促进我在哥伦比亚的新领导角色，2） 掌握对基因组和基因组表达数据进行计算分析的技能，3）加深我的 衰老生物学的知识，4）获得技能，成功地写我的第一个R 01补助金。总之，这次培训 格兰特通过科学建议和培训计划，将给我作为一名科学家蓬勃发展的资源 为阿尔茨海默病的研究做出贡献。 0925-0001/0002（2012年8月修订版）续页格式页