Biomarker Expression and Regulatory Haplotypes in Alzheimer's Disease

阿尔茨海默氏病的生物标志物表达和调节单元型

• 批准号: 8700271
• 负责人: Lynn Bekris
• 金额: $ 24.9万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700271
• 关键词: APP gene; Accounting; Active Sites; Age; Age of Onset; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein Precursor; Apolipoprotein E; Apolipoproteins; Binding; Biological; Biological Assay; Biological Markers; Brain; Brain region; Cerebrospinal Fluid; Characteristics; Cholinesterase Inhibitors; Complex; Deposition; Diagnosis; Disease; Distant; Early Diagnosis; Early Intervention; Ethnic Origin; Evaluation; Frontotemporal Dementia; Gender; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genetic Variation; Genomic DNA; Genotype; Haplotypes; Impaired cognition; In Vitro; Individual; Investigation; Late Onset Alzheimer Disease; Linear Regressions; Logistic Regressions; Luciferases; Mentors; Methods; MicroRNAs; Modeling; Molecular; Molecular Target; Nerve Degeneration; Neurodegenerative Disorders; Nucleic Acid Regulatory Sequences; Parkinson Disease; Pathogenesis; Phase; Phenotype; Phosphorylation; Population; Presenile Alzheimer Dementia; Prevalence; Production; Promoter Regions; Protein Precursors; Proteins; RNA Splicing; Regression Analysis; Regulation; Regulatory Element; Reporter; Research Personnel; Site; Staging; Techniques; Testing; Therapeutic; Training; Transcriptional Regulation; Translating; abstracting; career development; disease phenotype; disorder risk; endophenotype; improved; interest; mild cognitive impairment; mind control; novel; promoter; research and development; research study; tau Proteins; tau-1; tool; vector

Project Summary/Abstract The characteristic findings in Alzheimer's disease (AD) post-mortem brain (PMB) are degeneration of neurons together with extensive amounts of amyloid deposits (A¿42) (a cleavage product of the amyloid precursor protein encoded by the APP gene) and tau (encoded by the MAPT gene). Cerebrospinal fluid (CSF) A¿42 and tau levels can predict AD but have a limited reliability in discriminating AD from other neurodegenerative diseases. The apolipoprotein (APOE) ¿4 allele and age are currently the only factors strongly associated with late onset AD. The large gaps in our understanding of the genetic aspects of AD may include additional genetic factors that impact age of onset and phenotypic expression of late onset AD. Individual genetic findings (non- synonomous SNPs) associated with complex diseases, such as AD, are unlikely to fully explain the substantial impact of genetic variation on disease pathogenesis. Multilevel etiologic factors are likely to underlie complex diseases and may include multiple loci within and surrounding a gene that influence regulation of transcription and post-transcription, emphasizing the need for integrative evaluation of large genetic regions and correlations with protein biomarker levels as a means for predicting disease risk. This proposal focuses on the overall hypothesis that multiple genetic loci surrounding and within large gene regions act to regulate gene expression in an AD specific manner. During the mentored phase (K99) of this investigation the first aim is to find multiple loci or combinations of SNPs (haplotypes) surrounding and within the APOE, APP and MAPT genes that correlate with expression levels in CSF and PMB. Candidate genetic and protein biomarkers will expand beyond APOE, APP and MAPT genes to include other genes likely to be biologically relevant to neurodegenerative disease. The second aim is to demonstrate that putative regulatory haplotypes functionally impact expression by utilizing genomic DNA, containing a particular putative regulatory haplotype, as the active site of gene regulation in reporter and minigene assays. During the independent phase (R00), the final aim is to test regulatory haplotypes for their reliability in discerning between different AD phenotypes and between AD and other neurodegenerative diseases. Collectively, these proposed experiments are unique because they go beyond the simple correlation between core promoter loci and biomarker expression levels by using a combination of genetic, statistical and functional techniques to evaluate the influence of multiple loci within putative distant regulatory elements on AD relevant gene expression to find haplotypes that predict AD. The research and career development components of this K99/R00 application will provide the necessary training for the applicant to become a successful independent investigator who can integrate these techniques to improve our understanding of neurodegenerative disease risk.

项目摘要/摘要 阿尔茨海默氏病（AD）验尸后大脑（PMB）的特征发现是神经元的变性 加上大量的淀粉样蛋白沉积物（A€42）（淀粉样蛋白前体的裂解产物 蛋白质由App Gene编码）和Tau（由MAPT基因编码）。脑脊液（CSF）a¿42和 TAU水平可以预测AD，但在区分其他神经退行性的AD方面具有有限的可靠性 疾病。载脂蛋白（APOE）»4等位基因和年龄是目前与 发作广告。我们对AD遗传方面的理解的巨大差距可能包括其他遗传 影响发作年龄和表型表达的因素。个别遗传发现（非 与复杂疾病（例如AD）相关的同步SNP）不太可能完全解释实质性的 遗传变异对疾病发病机理的影响。多级病因因素可能是复杂的基础 疾病，可能包括影响转录调节的基因内外的多个基因座 和转录后，强调需要对大遗传区域进行综合评估和 与蛋白质生物标志物水平的相关性是预测疾病风险的一种手段。该提议重点是 总体假设，即多个遗传位置周围和大基因区域都可以调节基因 以广告为特定的方式表达。在此调查的物质阶段（K99）中，第一个目的是 要查找周围和apoE中的SNP（单倍型）的多个局部或组合，App和Mapt 与CSF和PMB中表达水平相关的基因。候选遗传和蛋白质生物标志物将 扩展超越APOE，APP和MAPT基因，包括其他可能在生物学上与之相关的基因 神经退行性疾病。第二个目的是证明假定的调节单倍型功能 通过使用基因组DNA（包含特定推定的调节单倍型）的影响表达，作为活性 报告基因调节位点在记者和小型测定法中。在独立阶段（R00）中，最终目标是 测试调节单倍型的可靠性，以辨别不同的AD表型和AD之间的可靠性 和其他神经退行性疾病。总的来说，这些提议的实验是独一无二的 除了核心启动子基因座与生物标志物表达水平之间的简单相关性外， 遗传，统计和功能技术的组合，以评估多个基因座的影响 假定的远处调节元素在AD相关基因表达上找到可以预测AD的单倍型。这 该K99/R00应用程序的研究和职业发展组件将提供必要的培训 适用的是成为成功的独立调查员，他们可以将这些技术整合到 提高我们对神经退行性疾病风险的理解。