A gene expression study of regional vulnerability in Alzheimer's disease

阿尔茨海默病区域脆弱性的基因表达研究

• 批准号: 7672394
• 负责人: Jeremy A Miller
• 金额: $ 3.01万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-10-01 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7672394
• 关键词: Affect; Aging; Alzheimer' s Disease; Amygdaloid structure; Amyloid beta-Protein; Apoptosis; Area; Atrophic; Bioinformatics; Biological Assay; Brain; Brain region; Candidate Disease Gene; Cell Communication; Cell Line; Cells; Cellular biology; Cerebellum; Cerebral cortex; Computing Methodologies; Custom; Data; Data Set; Dementia; Developmental Gene; Diffuse; Disease; Disease Progression; Down-Regulation; Early Diagnosis; Emotions; Gene Expression; Gene Mutation; Gene Targeting; Genes; Genetic; Genetic Heterogeneity; Genomics; Grant; Hippocampus (Brain); Human; In Situ Hybridization; In Vitro; Individual; Inflammatory Response; Ion Transport; Lead; Learning; Link; Long-Term Depression; Long-Term Potentiation; Malignant Neoplasms; Maps; Memory; Methodology; Methods; Microarray Analysis; Morphologic artifacts; Motor Cortex; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neuronal Dysfunction; Neuronal Plasticity; Neurons; Parietal Lobe; Pathology; Pathway Analysis; Pathway interactions; Pattern; Perception; Predisposition; Publishing; Pyramidal Cells; Relative (related person); Resolution; Risk Factors; Role; Sampling; Secondary to; Sensory; Structure; Synaptic Transmission; Testing; Tissues; United States; Validation; Visual; Weight; Work; association cortex; base; cell type; cohort; cost; design; disorder control; entorhinal cortex; extracellular; gene interaction; hippocampal pyramidal neuron; insight; interest; laser capture microdissection; network models; neuroprotection; normal aging; novel; presenilin-1; presenilin-2; prevent; protective effect; regional difference; research study; sensory cortex; tau Proteins; transcription factor; transcriptomics

DESCRIPTION (provided by applicant): An important issue in neurodegenerative disorders is the issue of regional vulnerability. Why are specific cell types in specific brain regions targeted first, when most of the underlying disease-causing genes are expressed ubiquitously? In the case of Alzheimer's disease (AD), PSEN1, PSEN2, and APP mutations lead to a typical pattern of neurodegeneration in most cases, starting with degeneration of CA1 hippocampal pyramidal cells, followed later by degeneration of the structurally similar CAS pyramidal neurons, posterior, superior parietal lobe, and eventually by degeneration of most of the cerebral cortices, sparing cerebellum and primary sensory cortices. Sporadic AD, where specific Mendelian mutations have not been identified, leads to essentially the same disease progression. We hypothesize that regions relatively invulnerable to AD pathology express patterns of genes that provide relative protection, and that gene expression changes in more vulnerable regions reflect their vulnerability. Similarly, susceptibility to neurodegeneration does not occur on a whole tissue level, but rather in specific cell types. Therefore, by comparing gene expression in structurally similar neurons or regions of the hippocampus (CA1 and CAS) that are differentially vulnerable to AD pathology, targets for AD neuroprotection and susceptibility will be uncovered. Healthy pyramidal cells will be extracted from both CA1, which is vulnerable to AD pathology, and CAS, which is relatively less vulnerable, in both controls and individuals with advanced AD using laser capture microdissection. Amplified cRNA from pools of cells in these regions will then be hybridized to custom microarrays, and analyzed for differentially expressed genes using standard methods. Additionally, the transcriptional networks specific to each region will be identified using weighted gene co-expression network analysis (WGCNA), a powerful new method for uncovering transcriptomic organization. In all, expression data will be collected under six conditions: 1) Control CA1, 2) CAS, and 3) visual pole, as well as 4) diseased CA1, 5) CAS, and 6) visual pole, where visual pole is included as a control brain region that remains essentially unaffected by AD. These data will be used to determine the transcriptional network related to relative protection and susceptibility in AD through regional comparisons and control/disease comparisons. By designing our experiment around finding neuroprotective genes, this experimental plan will uncover novel target genes for AD, which may have the potential for early diagnoses and treatment of AD.

描述（申请人提供）：神经退行性疾病中的一个重要问题是区域脆弱性的问题。当大多数基本引起疾病的基因无处不在时，为什么特定的大脑区域中的特定细胞类型首先是针对的？在阿尔茨海默氏病（AD），PSEN1，PSEN2和APP突变的情况下，在大多数情况下会导致典型的神经退行性模式，从CA1海马锥体细胞退化开始，然后随后在结构上相似的cas锥体神经元，上层，最终的sprietal parietal careation cas pyneries erseries of degeneration the Ca1海马锥体细胞，最终是结构上相似的cas层。小脑和主要感觉皮层。尚未鉴定出特定的孟德尔突变的零星AD导致基本相同的疾病进展。我们假设对AD病理学的区域表达提供相对保护的基因模式，并且基因表达在更脆弱的区域发生变化，反映了它们的脆弱性。同样，对神经变性的敏感性不会在整个组织水平上发生，而是在特定的细胞类型上发生。因此，通过比较在结构相似的神经元中的基因表达或海马（CA1和CAS）差异很容易受到AD病理学的影响，将发现AD神经保护和敏感性的靶标。健康的锥体细胞将从CA1中提取，这两种CA1都容易受到AD病理的影响，而CAS在使用激光捕获微分解的对照组和具有晚期AD的个体中相对较小的CAS。然后将这些区域中细胞池的扩增CRNA与自定义微阵列杂交，并使用标准方法对差异表达的基因进行了分析。此外，将使用加权基因共表达网络分析（WGCNA）来识别针对每个区域的转录网络，这是一种有力的新方法，用于揭示转录组组织。总共将在六个条件下收集表达数据：1）控制CA1，2）CAS和3）视觉极，以及4）患病的Ca1，5）CAS和6）视觉极，其中将视觉极作为对照脑区域，而对照脑区域基本不受AD的影响。这些数据将用于通过区域比较和对照/疾病比较来确定与AD相对保护和易感性相关的转录网络。通过设计我们的实验围绕寻找神经保护基因，该实验计划将发现AD的新靶基因，这可能有可能早期诊断和治疗AD。