Neurogenomics of Alzheimer's Disease and Aging

阿尔茨海默病和衰老的神经基因组学

• 批准号: 7112273
• 负责人: Dietrich A Stephan
• 金额: $ 50.35万
• 依托单位: TRANSLATIONAL GENOMICS RESEARCH INST
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7112273
• 关键词: Alzheimer' s disease; aging; apolipoprotein E; clinical research; cognition disorders; functional /structural genomics; gene expression; genome; histopathology; human genetic material tag; human old age (65+); human tissue; laser capture microdissection; molecular pathology; neurogenetics; postmortem

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) affects a large proportion of the world's population and is primarily a disease of old age. There is little known about the early molecular pathogenesis of AD leading to the characteristic dementia. Increased knowledge of the etiologic processes leading to dementia would allow improved diagnostics and targeted therapeutics. This proposal is multifaceted and seeks to elucidate 1) what differentiates AD from normal aging processes and other dementias of old age, 2) why individuals with certain genetic backgrounds (ApoE4 alleles) are more likely to become affected (inter-individual differences), 3) and what happens at the cellular and subcellular level in response to dementia-inducing stimuli (plaques and tangles)(intra-individual differences). Taken together the expression profiling data set generated on laser capture microdissected (LCM) cells from carefully stratified patient cohorts should provide unique insight into the AD phenotype. Specific hypotheses related to energy metabolism will be validated by multiple techniques (by immunohistochemistry on independent tissues and at the functional level using neuronal cell cultures and siRNAs). These results will be made available to the general public within 6 months of generation via the most established relational database for array data, the NINDS/NIMH array consortium repository. The applicants are uniquely qualified to perform a large-scale collaborative study of this type. Working closely in collaboration with 3 Alzheimer's Disease Centers (ADCs), the PIs will have access to tissue sections from the appropriate cohorts. The use of tissue sections (as opposed to large heterogeneous pieces of brain) and LCM as the starting reagents for the expression profiling will allow generation of high quality data while not depleting the banked national resource of brains. The PI is the Chairman of a National consortium of expression profiling facilities which generate extremely high quality data on large numbers of neurological phenotypes. Integration of this data set into that repository will increase the value of the AD data set exponentially because of the increased number of comparisons which can be generated using pre-existing data. The group also has access to sophisticated validation technologies. In all, the partnership of leaders in the AD field, the national resources within the ADCs, and the genomics expertise at TGen should allow rapid progress in understanding the etiology of AD dementia.

描述（由申请人提供）：阿尔茨海默氏病（AD）影响了世界人口的很大一部分，主要是老年疾病。关于导致特征性痴呆的AD的早期分子发病机理鲜为人知。对导致痴呆症的病因学过程的知识增加将可以改善诊断和靶向治疗剂。该提议是多方面的，并试图阐明1）AD与正常衰老过程和老年的其他痴呆症有所区别，2）为什么具有某些遗传背景（APOE4等位基因）的个体更有可能受到影响（个性间差异）（间个性差异），3），以及在细胞和下型刺激性（Pla-nignia-Intera-Intera-Intera-Intera-Intera-Intera-Intrual-Intera-Intrual-Intrual-Intrial-Intrual-Intrual-Intrual-Intrual-Intrual-Intrual-Intrual-Intera）（Pla）（差异）。总而言之，从精心分层的患者同类中产生的激光捕获（LCM）细胞产生的表达分析数据集应为AD表型提供独特的见解。与能量代谢相关的特定假设将通过多种技术（通过独立组织的免疫组织化学以及使用神经元细胞培养物和siRNA的功能水平）来验证。这些结果将在生成6个月内通过阵列数据（NINDS/NIMH数组财团存储库）的最建立的关系数据库提供给公众。申请人具有独特的资格，可以对此类进行大规模的协作研究。与3个阿尔茨海默氏病中心（ADC）密切合作，PIS将可以从适当的队列中获取组织切片。使用组织切片（与大脑的大型碎片相反）和LCM作为表达分析的起始试剂将允许产生高质量的数据，而不会耗尽大脑的银行国家资源。 PI是国家表达分析设施联盟的主席，该联盟在大量神经表型上产生了极高的数据。将此数据集的集成到该存储库中将呈指数级增加AD数据集的值，因为可以使用预先存在的数据生成的比较数量增加。该小组还可以访问复杂的验证技术。总的来说，AD领域的领导者合作伙伴关系，ADC中的国家资源以及TGEN的基因组学专业知识应允许在理解AD痴呆症的病因方面的快速进步。