Genetic Resilience to the Clinical Manifestation of Dementia

 描述(由申请者提供)：该项目将确定预测个人对阿尔茨海默病(AD)或脑血管疾病引起的认知障碍的恢复力的遗传因素。在尸检中，大约30%认知正常的人具有AD或脑血管疾病的病理特征。然而，到目前为止，很少有研究关注可能对这种韧性起作用的遗传因素。这个项目的目标是描绘无症状AD的遗传结构。这些新基因的识别将为临床干预提供靶点，旨在激活对神经病理的天然生物防御。这项工作将应用一种创新的方法来计算预测的基因表达水平，而不是仅仅依赖全基因组关联研究(GWAS)分析。我还将利用两个尸检数据库：国家阿尔茨海默氏症协调中心(n=882)和宗教教团研究/记忆和老龄化项目(n=954)。我的指导团队在这些数据集方面拥有丰富的经验，并将通过研究方法和并行培训计划提供专家指导。我的中心假设是，遗传效应将预测对阿尔茨海默病和脑血管病变的破坏性影响的认知弹性。基于这一假设，这项应用的主要目标将识别和复制(1)预测AD病理的认知弹性，(2)预测认知弹性的遗传效应 脑血管病理学。补充培训计划将通过强调以下培训内容领域，使我具备必要的技能，以建立专注于遗传韧性的独立研究生涯：(1)神经病理学，(2)弥合基因型与基因表达差距的先进生物信息学，以及(3)阿尔茨海默病和血管性痴呆的临床特征。导师团队由上述每个内容领域的专家组成。范德比尔特记忆和阿尔茨海默氏症中心的跨学科培训计划以及范德比尔特大学医学中心提供的尖端计算和基因组资源将加强他们的专家培训。这些实践和智力资源共同提供了理想的培训环境。我的主要导师安吉拉·杰斐逊博士有很强的资助历史以及所有的财政和智力资源 需要支持我向独立的过渡。这些广泛的资源将使我能够以助理教授的身份100%地致力于研究和职业发展。这将确保我完全准备好在拟议的获奖期内竞争独立资金(R01)。

 DESCRIPTION (provided by applicant): This project will identify genetic factors that predict individual resilience to cognitive impairment arising from Alzheimer's disease (AD) or cerebrovascular disease. At autopsy, approximately 30% of cognitively normal individuals have the pathological features of AD or cerebrovascular disease. Yet, to date very little research has focused on the genetic factors that might contribute to such resilience. The objective of this project is to delineate the genetic architecture of asymptomatic AD. The identification of such novel genes will provide targets for clinical intervention aimed at activating natural biological defenses to neuropathology. This work will apply an innovative method to calculate predicted-gene-expression levels rather than relying solely on genome-wide association study (GWAS) analyses. I will also leverage 2 autopsy datasets: the National Alzheimer's Coordinating Center (n=882) and the Religious Orders Study/Memory and Aging Project (n=954). My mentorship team has extensive experience with these datasets and will provide expert guidance through the research methods and parallel training plan. My central hypothesis is that genetic effects will predict cognitive resilience to the damaging effects of AD and cerebrovascular pathologies. Based on this hypothesis, the primary aims of this application will identify and replicate genetic effects that (1) predict cognitive resilience to AD pathology, and (2) predict cognitive resilience to cerebrovascular pathology. The complementary training plan will equip me with the skills necessary to build out an independent research career focused on genetic resilience by emphasizing the following training content areas: (1) neuropathology, (2) advanced bioinformatics to bridge the gap from genotype to gene expression, and (3) the clinical characterization of AD and vascular dementia. The mentor team is made up of experts in each of these content areas. Their expert training will be augmented by the interdisciplinary training program at the Vanderbilt Memory and Alzheimer's Center, and the cutting edge computational and genomic resources available at Vanderbilt University Medical Center. Together, these practical and intellectual resources provide the ideal training environment. My primary mentor, Dr. Angela Jefferson, has a strong funding history and all the financial and intellectual resources needed to support my transition to independence. These extensive resources will allow me to dedicate 100% protected effort as an Assistant Professor to focus on research and career development. This will ensure that I am fully prepared to compete for independent funding (R01) over the course of the proposed award period.