Neurogenomics of Alzheimer's Disease and Aging

描述（由申请人提供）：阿尔茨海默病（AD）影响世界人口的很大一部分，主要是一种老年疾病。目前对AD导致特征性痴呆的早期分子发病机制知之甚少。增加导致痴呆的病因学过程的知识将允许改进诊断和靶向治疗。该建议是多方面的，旨在阐明1）AD与正常衰老过程和其他老年痴呆症的区别，2）为什么具有某些遗传背景（ApoE 4等位基因）的个体更容易受到影响（个体间差异），3）以及在细胞和亚细胞水平上发生了什么反应痴呆诱导刺激（斑块和缠结）（个体内差异）。总之，从仔细分层的患者队列的激光捕获显微切割（LCM）细胞上生成的表达谱数据集应该提供对AD表型的独特见解。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和使用神经元细胞培养物和siRNA在功能水平上）进行验证。这些结果将在生成后的6个月内通过最成熟的阵列数据关系数据库NINDS/NIMH阵列联盟存储库向公众提供。申请人是唯一有资格进行这种类型的大规模合作研究。与3个阿尔茨海默病中心（ADC）密切合作，PI将获得适当队列的组织切片。使用组织切片（而不是大的异质性脑片）和LCM作为表达谱分析的起始试剂将允许产生高质量的数据，同时不会耗尽国家储备的脑资源。PI是国家表达谱设施联盟的主席，该联盟产生了大量神经表型的极高质量数据。将该数据集集成到该存储库中将以指数方式增加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的数量增加。该集团还拥有先进的验证技术。总之，AD领域领导者的伙伴关系，ADC内的国家资源以及TGen的基因组学专业知识应该可以在了解AD痴呆症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.