Neurogenomics of Alzheimer's Disease and Aging

描述(申请人提供)：阿尔茨海默病(AD)影响着世界上很大一部分人口，主要是一种老年病。阿尔茨海默病导致特征性痴呆的早期分子发病机制知之甚少。增加对导致痴呆症的病因过程的了解将有助于改进诊断和有针对性的治疗。这一建议是多方面的，旨在阐明1)阿尔茨海默病与正常衰老过程和其他老年痴呆的区别，2)为什么具有特定遗传背景的人更容易受到影响(个体间的差异)，3)在细胞和亚细胞水平上对诱发痴呆症的刺激(斑块和缠结)的反应(个体内的差异)。综上所述，来自仔细分层的患者队列的激光捕获显微解剖(LCM)细胞产生的表达谱数据集应该提供对AD表型的独特洞察。与能量代谢相关的特定假说将通过多种技术来验证(通过对独立组织的免疫组织化学以及使用神经元细胞培养和siRNA在功能水平上的验证)。这些结果将在生成后6个月内通过最成熟的阵列数据关系数据库--NINDS/NIMH阵列联盟储存库--向公众提供。申请者是唯一有资格进行这种类型的大规模合作研究的人。与3个阿尔茨海默病中心(ADC)密切合作，PI将能够获得适当队列的组织切片。使用组织切片(而不是大块不同种类的脑片)和LCM作为表达谱的起始试剂，将允许生成高质量的数据，同时不会耗尽国家储备的大脑资源。PI是一个全国表情分析设施联盟的主席，该联盟产生关于大量神经表型的极高质量的数据。将该数据集集成到该存储库中将以指数级增加AD数据集的价值，因为可以使用预先存在的数据生成的比较次数增加。该组织还可以使用复杂的验证技术。总而言之，AD领域的领导者之间的伙伴关系、ADDC内的国家资源以及TGen的基因组学专业知识应该会在理解AD痴呆的病因方面取得快速进展。

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.