Genetic Resilience to the Clinical Manifestation of Dementia

 描述（由申请人提供）：该项目将确定预测个体对阿尔茨海默病（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%的认知正常个体具有AD或脑血管疾病的病理特征。然而，迄今为止，很少有研究集中在可能有助于这种恢复力的遗传因素上。本项目的目的是描绘无症状AD的遗传结构。这些新基因的鉴定将为旨在激活神经病理学的天然生物防御的临床干预提供靶点。这项工作将采用一种创新的方法来计算预测的基因表达水平，而不是仅仅依赖于全基因组关联研究（GWAS）分析。我还将利用2个尸检数据集：国家阿尔茨海默病协调中心（n=882）和宗教秩序研究/记忆和衰老项目（n=954）。我的导师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AD和脑血管病变的破坏性影响的认知弹性。基于这一假设，本申请的主要目的是鉴定和复制遗传效应，其（1）预测对AD病理学的认知恢复力，和（2）预测认知恢复力 脑血管病理学补充培训计划将使我具备必要的技能，以建立一个独立的研究生涯，重点是遗传弹性，强调以下培训内容领域：（1）神经病理学，（2）先进的生物信息学，以弥合从基因型到基因表达的差距，以及（3）AD和血管性痴呆的临床特征。导师团队由这些内容领域的专家组成。他们的专家培训将通过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的尖端计算和基因组资源得到加强。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，有一个强大的资金历史和所有的财政和智力资源 需要支持我向独立过渡这些广泛的资源将使我能够作为助理教授致力于100%的保护努力，专注于研究和职业发展。这将确保我完全准备好在拟议的奖励期间竞争独立资金（R 01）。

 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.