Using long-range technologies as a multi-omic approach to understand Alzheimer's disease in brain tissue

使用远程技术作为多组学方法来了解脑组织中的阿尔茨海默病

• 批准号: 10030834
• 负责人: Mark T W Ebbert
• 金额: $ 61.93万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2020-10-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10030834
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease risk; Automobile Driving; Biology; Brain; Brain Diseases; Clinic; Complement; Complex; DNA; DNA Structure; DNA mapping; DNA sequencing; Data; Data Set; Detection; Development; Diagnostic; Disease; Genes; Goals; Grant; Individual; Intervention; Methods; Modification; Molecular; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Nucleotides; Optics; Phenotype; Play; Protein Isoforms; Proteins; RNA; RNA Splicing; Research Personnel; Role; Sampling; Symptoms; Technology; The Sun; Therapeutic; Validation; Variant; Work; advanced disease; brain health; brain tissue; cohort; design; differential expression; disease diagnosis; frontal lobe; gain of function; genome-wide; insight; mind control; multiple omics; outcome forecast; programs; targeted treatment; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT Our long-term goal is to help develop a meaningful therapeutic and pre-symptomatic diagnostic for Alzheimer’s disease because, while a disease-altering therapeutic is essential, it will not be sufficient without a diagnostic that identifies disease before symptoms onset. We seek to contribute to these long-term goals by helping identify specific molecular modifications, and therefore specific mechanisms, driving disease using long-range optical DNA mapping and sequencing technologies. Unfortunately, most Alzheimer’s disease genes are only implicated through common non-functional variants, and it is still unclear how most Alzheimer’s disease genes are involved in disease. Likewise, individual RNA isoforms in diseased brains for top Alzheimer’s disease genes and their involvement in disease are poorly understood. Functional variants and RNA sequencing at the isoform level in diseased brain tissue will provide specific mechanisms to target for therapeutics and diagnostics. Large short-read sequencing efforts are already ongoing to identify small functional variants involved in Alzheimer’s disease, but structural DNA variants—many of which directly affect downstream RNA and proteins—also cause neurodegenerative diseases. We hypothesize that undiscovered SVs and aberrant RNA isoforms play a direct role in Alzheimer’s disease. A thorough study in diseased brain using long-range DNA and RNA technologies will complement current short-read efforts, providing important disease insights.

项目摘要/摘要 我们的长期目标是帮助开发有意义的治疗和症状诊断 对于阿尔茨海默氏病而言，虽然改变疾病的疗法是必不可少的 足够没有诊断性的诊断症状发作之前就可以识别疾病。我们寻求 通过帮助确定特定的分子修饰，并为这些长期目标做出贡献 因此，特定机制，使用远程光学DNA映射驱动疾病和 测序技术。不幸的是，大多数阿尔茨海默氏病基因仅实施 通过常见的非功能变体，目前尚不清楚大多数阿尔茨海默氏病如何 基因参与疾病。同样，在解剖大脑中的单个RNA同工型 阿尔茨海默氏病基因及其对疾病的参与知之甚少。功能 在解剖脑组织中的同工型水平上的变体和RNA测序将提供特定 靶向治疗和诊断的机制。大型简读测序工作是 已经开始识别阿尔茨海默氏病涉及的小功能变体，但结构性 DNA变体（其中许多直接影响下游RNA和蛋白质）也导致 神经退行性疾病。我们假设未发现的SV和异常RNA同工型 在阿尔茨海默氏病中发挥直接作用。使用远距离的详尽研究 DNA和RNA技术将补充当前的简短努力，提供重要 疾病见解。