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

项目主任/首席调查员(最后、第一、中间)：泰奇，安德鲁·富兰克林 项目总结： 这是一笔培训补助金，它将给我提供资源，让我发展成为一名学术内科医生-科学家。我的龙- 学期目标是研究阿尔茨海默病(AD)和老年人的神经退行性疾病 老化的大脑，并将其与我作为神经病理学家的临床角色(至少占我75%的时间)结合起来 致力于研究)。这笔赠款既有科学建议部分，也有培训部分。这个 科学提案部分将提出两个问题。首先，我会问一下，基因上是否有差异 皮质β-淀粉样蛋白负荷相似的AD患者和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，β- 淀粉样蛋白也被证明会导致DNA甲基化的改变。然而，“病理对照”有 β-淀粉样蛋白水平升高，但不是痴呆症。由于病理对照的β-淀粉样蛋白水平升高， β-淀粉样蛋白已被证明可以引起DNA甲基化的改变，病理对照可能有一些 通常与AD相关的甲基化异常，不会直接导致痴呆症。通过比较AD 脑组织到病理对照组织，我希望梳理出相关基因甲基化的变化 与痴呆症的存在关系最强。其次，我会问DNA甲基化是否有变化 在AD病理环境中预测认知状态恶化，使用的患者群体是 因脑积水而被分流。总而言之，这些实验将有助于梳理出异常的联系 阿尔茨海默病患者认知功能受损与DNA甲基化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)。在我的临床训练结束后的最后几年里，我精通了实验 神经科学(即“湿实验室”工作)。这笔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，重点是应用这些技术 神经退化和大脑老化的技术。此外，这笔培训补助金与我的 晋升为哥伦比亚大学纽约脑库联席主任。我要完成四个训练 在此资助过程中的目标：1)获得一套技能，以促进我在哥伦比亚大学的新领导角色，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)深化我的 对衰老生物学的了解，获得了成功撰写我的第一笔R01赠款的技能。总而言之，这次培训 格兰特，通过科学建议和培训计划，将给我资源，让我成为一名科学家 并为阿尔茨海默病的研究做出贡献。 0925-0001/0002(08/12版)页面续格式页面

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