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.

项目概要/摘要 阿尔茨海默病 (AD) 死后大脑 (PMB) 的特征性发现是神经元退化 连同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） APP 基因编码的蛋白质）和 tau（MAPT 基因编码）A¿ 42 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 载脂蛋白 (APOE) ¿ 4 等位基因和年龄是目前与此密切相关的唯一因素 我们对 AD 遗传方面的理解存在巨大差距，可能还包括其他遗传因素。 影响晚发 AD 发病年龄和表型表达的因素（非-） 与 AD 等复杂疾病相关的同义 SNP 不太可能完全解释其实质意义 遗传变异对疾病发病机制的影响可能是复杂的。 疾病，可能包括影响转录调控的基因内部和周围的多个位点 和转录后，强调对大遗传区域进行综合评估的必要性 与蛋白质生物标志物水平的相关性作为预测疾病风险的手段。 总体假设：大基因区域周围和内部的多个遗传位点起到调节基因的作用 在本次调查的指导阶段（K99），第一个目标是以 AD 特定方式表达。 查找 APOE、APP 和 MAPT 周围和内部的多个位点或 SNP（单倍型）组合 与 CSF 和 PMB 表达水平相关的基因将成为候选遗传和蛋白质生物标志物。 扩展到 APOE、APP 和 MAPT 基因之外，包括可能与生物相关的其他基因 第二个目标是证明假定的调节单倍型的功能。 通过利用基因组 DNA（包含特定的假定调节单倍型）作为活性物质来影响表达 报告基因和小基因检测中基因调控的位点 在独立阶段 (R00)，最终目标是。 测试调节单倍型在区分不同 AD 表型和 AD 之间的可靠性 总的来说，这些拟议的实验是独一无二的，因为它们 超越核心启动子位点和生物标志物表达水平之间的简单相关性 结合遗传、统计和功能技术来评估多个位点的影响 AD 相关基因表达的假定远程调控元件，以找到预测 AD 的单倍型。 该 K99/R00 应用程序的研究和职业发展部分将提供必要的培训 使申请人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了解。