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

基本信息

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
项目类别：
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&apos 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

项目摘要

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

计划总监/首席调查员（最后，第一，中间）：Teich，Andrew Franklin 项目摘要：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。我的长期术语目标是进行侧重于阿尔茨海默氏病（AD）和神经退行性疾病的研究大脑衰老，并将其与我作为神经病理学家的临床角色相结合（我的时间至少有75％致力于研究）。该赠款具有科学提案部分以及培训组成部分。这科学提案部分将提出两个问题。首先，我会问基因是否存在差异 AD患者与具有相似皮质β-淀粉样蛋白负荷的认知正常患者之间的甲基化（“ partiologoly Controls”）。已显示AD患者在DNA甲基化中有异常，β- 淀粉样蛋白也已显示导致DNA甲基化的改变。但是，“病理控制”具有 β-淀粉样蛋白水平升高，但不痴呆。由于病理对照的β-淀粉样蛋白水平升高，并且 β-淀粉样蛋白已显示导致DNA甲基化改变，病理控制可能具有一定的DNA 通常与不会直接引起痴呆的AD相关的甲基化异常。通过比较广告脑组织到病理控制组织，我希望取消相关的基因甲基化的变化痴呆症的存在最强。其次，我会问是否有DNA甲基化发生变化可以预测在AD病理中担心认知状况，使用患者人群被晒黑了。总之，这些实验将有助于取消异常的关联 DNA甲基化AD中的认知受损。我的博士学位论文是在计算神经科学实验室中（即 “干lab”工作）。在临床训练熟练精通实验后，我已经度过了过去几年神经科学（即“湿地”工作）。这项培训赠款将利用这一背景，并培训我分析的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变性和衰老大脑的技术。此外，这项培训赠款与我的高程到哥伦比亚大学纽约大脑银行联合导演。我将完成四个训练在这笔赠款过程中的目标； 1）获得一项技能，以促进我在哥伦比亚的新领导角色，2）获取对基因组和基因组表达数据进行计算分析的技能，3）加深我衰老生物学知识，4）获取成功撰写我的第一个R01赠款的技能。总之，这项培训通过科学建议和培训计划，格兰特将为我提供资源，以蓬勃发展并为阿尔茨海默氏病研究做出贡献。 0925-0001/0002（修订版08/12）页面延续格式页面