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: 7272679
• 负责人: TRAVIS L DUNCKLEY
• 金额: $ 47.9万
• 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 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7272679
• 关键词: Affect; Age; Aging; Aging-Related Process; Alleles; Alzheimer' s Disease; Amyloid; Anterior; Apolipoprotein E; Arizona; Brain; Brain region; Cataloging; Catalogs; Categories; Cells; Cessation of life; Chairperson; Characteristics; Class; Classification; Clinical; Collaborations; Communities; Corpus callosum splenium; Coupled; Cultured Cells; Data; Data Quality; Data Set; Databases; Dementia; Deposition; Diagnostic; Disease; Distant; Educational Status; End Point Assay; Energy Metabolism; Ensure; Etiology; Exposure to; Female; Freezing; Frozen Sections; Gene Expression; Gene Expression Profile; Gene Expression Profiling; General Population; Generations; Genes; Genetic; Geniculate body structure; Genomics; Genotype; Heterogeneity; Hippocampus (Brain); Histopathology; Immunohistochemistry; In Vitro; Individual; Individual Differences; Knowledge; Lasers; Medial; Metabolic; Microscopy; Molecular; Molecular Profiling; Neurofibrillary Tangles; Neurologic; Neurons; Numbers; Online Systems; Pathogenesis; Pathologic; Pathology; Patients; Persons; Phenotype; Population; Principal Investigator; Process; Proteins; Qualifying; Reagent; Research Design; Resources; Sample Size; Sampling; Stimulus; Stratification; Structure of genu of corpus callosum; Structure of middle temporal gyrus; Structure of superior frontal gyrus; Techniques; Temporal Lobe; Testing; Tissues; Universities; Validation; Visual Cortex; Washington; Work; age group; age related; apolipoprotein E-4; area striata; base; cohort; disease phenotype; entorhinal cortex; foot; improved; insight; male; mild neurocognitive impairment; neocortical; neurofibrillary tangle formation; normal aging; programs; repository; response; statistics; tau Proteins; technology validation; therapeutic target

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）：阿尔茨海默病（AD）影响世界上很大一部分人口，并且主要是一种老年疾病。人们对 AD 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。该提案是多方面的，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（ApoE4 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对诱发痴呆的刺激（斑块和缠结）做出反应时会发生什么（个体内） 差异）。将来自仔细分层的患者群体的激光捕获显微切割 (LCM) 细胞生成的表达谱数据集放在一起，应该可以提供对 AD 表型的独特见解。与能量代谢相关的具体假设将通过多种技术进行验证（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 在功能水平上进行验证）。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 阵列联盟存储库）向公众提供。申请人具有进行此类大规模合作研究的独特资格。通过与 3 个阿尔茨海默氏病中心 (ADC) 密切合作，PI 将能够获取来自适当队列的组织切片。使用组织切片（而不是大的异质脑块）和 LCM 作为表达谱的起始试剂将能够生成高质量的数据，同时不会耗尽国家的大脑资源。 PI 是国家表达谱设施联盟的主席，该设施生成大量神经表型的极高质量数据。将此数据集集成到该存储库中将成倍增加 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数量增加。该小组还可以获得先进的验证技术。总而言之，AD 领域领导者的合作、ADC 内的国家资源以及 TGen 的基因组学专业知识应该有助于在了解 AD 痴呆的病因方面取得快速进展。