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: 8849625
• 负责人: Lynn Bekris
• 金额: $ 17.09万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8849625
• 关键词: Biomarker; Expression; Regulatory; Haplotypes; Alzheimer

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 阿尔茨海默病(AD)死后脑(PMB)的特征表现是神经元变性 以及大量的淀粉样沉积(A？42)(淀粉样前体的切割产物 由APP基因编码的蛋白质)和tau(由MAPT基因编码)。脑脊液(CSF)A42和 Tau水平可以预测AD，但在区分AD和其他神经退行性疾病方面的可靠性有限 疾病。载脂蛋白(APOE)？4等位基因和年龄是目前唯一与 晚发性阿尔茨海默病。我们对阿尔茨海默病遗传方面的理解上的巨大差距可能包括额外的基因 影响晚发性AD发病年龄和表型表达的因素。个人遗传发现(非 与阿尔茨海默病等复杂疾病相关的同义词SNP)不太可能完全解释 基因变异对疾病发病机制的影响。多层次的病因可能是复杂的基础 疾病，可能包括影响转录调控的基因内部和周围的多个基因位点 和转录后，强调需要对大的基因区域和 与蛋白质生物标记物水平的相关性作为预测疾病风险的一种手段。这项提案的重点是 大基因区域周围和大基因区域内的多个遗传位点对基因起调控作用的总体假设 以特定于AD的方式表达。在本次调查的指导阶段(K99)，第一个目标是 寻找APOE、APP和MAPT周围和内部的多个SNPs(单倍型)或组合 与脑脊液和PMB中表达水平相关的基因。候选遗传和蛋白质生物标记物将 扩展到APOE、APP和MAPT基因之外，包括其他可能与生物相关的基因 神经退行性疾病。第二个目标是从功能上证明假定的调控单倍型 通过利用基因组DNA影响表达，基因组DNA包含特定的假定调节单倍型作为活性 报告和微基因分析中的基因调控位点。在独立阶段(R00)，最终目标是 测试调节性单倍型在区分不同AD表型和AD之间的可靠性 以及其他神经退行性疾病。总的来说，这些拟议的实验是独一无二的，因为它们 除了核心启动子基因座和生物标记物表达水平之间的简单相关性之外，还使用了 结合遗传、统计和功能技术评估多个基因座在体内的影响 推测AD相关基因表达的远距离调控元件，以寻找预测AD的单倍型。这个 K99/R00应用程序的研究和职业发展部分将提供必要的培训 让申请者成为一名成功的独立调查员，能够将这些技术整合到 提高我们对神经退行性疾病风险的理解。