Generating Blood-based Diagnosis for Alzheimer Disease

阿尔茨海默病的血液诊断

• 批准号: 8197930
• 负责人: EUGENIA WANG
• 金额: $ 82.27万
• 依托单位: ADVANCED GENOMIC TECHNOLOGY, LLC
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197930
• 关键词: 3' Untranslated Regions; Address; Age; Aging; Alzheimer' s Disease; Apoptosis; Autopsy; Back; Binding; Biogenesis; Biological Assay; Biological Markers; Blood; Boxing; Brain; Brain Pathology; CDK4 gene; Caloric Restriction; Caregivers; Cell Cycle; Cells; Cerebrospinal Fluid; Code; Cohort Studies; DNA; DNA Repair; Deacetylase; Diagnosis; Diagnostic; Disease; Down-Regulation; Elderly; Equilibrium; Evaluation; Exhibits; Family; Feasibility Studies; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Genotoxic Stress; Goals; Healthcare; Homeostasis; Individual; Investigation; Investments; Knowledge; Lead; Link; Longevity; Magnetic Resonance Imaging; MicroRNAs; Modeling; Molecular; Molecular Profiling; Monitor; Mononuclear; Neurofibrillary Tangles; Neuropsychological Tests; Oxidation-Reduction; Oxidative Stress; Participant; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Phase; Physiological; Pilot Projects; Plasma; Positron-Emission Tomography; Printing; Production; Protein Family; Proteins; Psychological Tests; RNA; Repression; Research; Resveratrol; Risk; Sampling; Science; Screening procedure; Senile Plaques; Serum; Signal Transduction; Societies; Specimen; Stress; Synapses; Testing; Translations; Untranslated RNA; Up-Regulation; Work; amyloid precursor protein processing; base; cohort; cyclin E2; drug efficacy; feeding; foot; gene repression; indexing; interest; meetings; member; novel; novel diagnostics; polyphenol; protein expression; public health relevance; red wine; repository; response to injury; senescence; success; tau Proteins; tau aggregation; tool; trend

DESCRIPTION (provided by applicant): The present lack of blood-based diagnosis requires AD patients to be subjected to either invasive spinal fluid (CSF) tapping, expensive MRI or PET imaging, or arduous psychological testing, all unsuitable and costly for our elderly. Strategically, we shall address this unmet need by generating systemic biomarkers detectable in peripheral mononuclear cells (PBMC) and serum/plasma, focusing on two classes of molecules, micro- RNAs and their target genes, which generally exhibit an inverse relationship because the former noncoding RNA functions by partially repressing the latter"s expression as a "dimmer switch", via binding either at the co- ding region of the message, thus degrading it, or at the 3"-untranslated region, to inhibit translation. Thus, key microRNAs and their targets can serve as disease biomarkers, in "see-saw" balance, applicable for new diagnostics and/or therapy. Our pilot study with a small cohort of 16 AD and 16 age-matched normal elderly controls (NEC) revealed: 1. Predominant down-regulation of gene expression at the message level in AD PBMC; and 2. Correlated up-regulation of microRNA (miR) expression in PBMC of the same individuals. In this proposal, we focus on a specific up-regulated microRNA, miR-34a, whose known targets are SIRT1, cdk4, cdk6, cyclin E2, bcl2, etc. SIRT1 is a member of the 7-member Silent Information Regulator protein family. Caloric restriction extends longevity through triggering expression of SIRT1, which can also be mimicked by resveratrol, a red wine polyphenol. SIRT1 reduction is linked to accumulation of Tau and A242 production, two hallmarks of AD etiopathogenesis. Thus, we suggest that in AD there is a systemic effect detectable in PBMC and serum/plasma; up-regulated miR-34a may induce down-regulation of SIRT1, with attendant pathophysiologic results. In this proposal, we plan to generate for this "see-saw" of changes miR-34a/SIRT1 Target Pair Ratio (TPR) indices, to quantify both disease presence as well as progress; the indices should also provide an unprecedented evaluation of drug efficacy. This Fast-track proposal of two phases is planned with our existing small cohort study as the roadmap for the larger cohort investigation: Phase I of six months with our existing small 16 AD and 16 NEC sample cohorts to: Aim 1. study possible down-regulation of miR-34a"s known targets; and Aim 2. develop a feasibility study of pilot miR-34a/SIRT1 TPR-indices; and Phase II of two years with larger cohorts of 200 AD and 200 NEC participants: Aim 1.Establish a Bio-Repository of PBMC-DNA, -RNA & -protein specimens, and serum/plasma samples for assays in Aims 2 & 3; Aim 2. Generate PBMC-based miR34a/SIRT1 (& other targets) TPR indices; and Aim 3. Perform feasibility study to develop serum/plasma-based miR- 34a/SIRT1-TPR indices. Success of this project will allow us to generate PBMC- and serum-based miR-TPR indices as personalized diagnostics for AD victims, meeting an urgent need in health care, a huge gain for disease victims, their caregivers, and our society at large. PUBLIC HEALTH RELEVANCE: At present, the absence of any blood-based diagnosis for Alzheimer"s disease (AD) requires patients to enduring arduous neuropsychological testing, invasive cerebrospinal fluid tapping, and/or expensive MRI or PET imaging, with definitive diagnosis deferred until brain autopsy. Our preliminary findings, based on new science concerning a novel molecular species, microRNAs (miR) and their "see-saw" partial repression of the expression of their target gene(s), suggest that potential disease biomarkers for AD are detectable systemical- ly in peripheral blood mononuclear cells and/or serum/plasma, and may be quantified as miR-Target Pair Ra- tios (TPR). Our plan is to define AD-specific TPR indices, initially focusing on miR-34a and its target, SIRT1, whose reduction is known to be associated with increased Tau and A242, two hallmarks of AD etiopathogene- sis; our ultimate goal is a "Tool-Box" of TPR indices, miR-34a/SIRT1-TPR being the first such AD diagnostic, indicating not only disease presence, but also its progress (and even drug efficacy monitoring), a huge strate- gic gain for the victims of this costly disease, and our society at large!

描述（由申请人提供）：目前缺乏基于血液的诊断，需要 AD 患者接受侵入性脊髓液 (CSF) 采集、昂贵的 MRI 或 PET 成像，或艰巨的心理测试，所有这些对于我们的老年人来说都是不合适且昂贵的。从战略上讲，我们将通过生成可在外周单核细胞（PBMC）和血清/血浆中检测到的系统生物标志物来解决这一未满足的需求，重点关注两类分子：微小RNA及其靶基因，它们通常表现出反比关系，因为前者非编码RNA的功能是通过部分抑制后者的表达作为“调光开关”，通过结合在信息的编码区域，从而降解它，或者结合在3”-非翻译区域，以抑制 翻译。因此，关键的 microRNA 及其靶标可以作为疾病生物标志物，在“拉锯”平衡中适用于新的诊断和/或治疗。我们对一小群 16 名 AD 患者和 16 名年龄匹配的正常老年对照 (NEC) 进行的初步研究表明： 1. AD PBMC 中信息水平的基因表达显着下调； 2. 同一个体的 PBMC 中 microRNA (miR) 表达的相关上调。在本提案中，我们重点关注一种特异性上调的 microRNA miR-34a，其已知靶标有 SIRT1、cdk4、cdk6、cyclin E2、bcl2 等。SIRT1 是沉默信息调节蛋白家族 7 成员中的一员。热量限制通过触发 SIRT1 的表达来延长寿命，白藜芦醇（一种红酒多酚）也可以模仿 SIRT1 的表达。 SIRT1 的减少与 Tau 和 A242 产生的积累有关，这是 AD 发病机制的两个标志。因此，我们认为在 AD 中，PBMC 和血清/血浆中存在可检测到的全身效应；上调的 miR-34a 可能会诱导 SIRT1 的下调，从而产生病理生理学结果。在本提案中，我们计划针对这种“拉锯”变化生成 miR-34a/SIRT1 靶标对比率 (TPR) 指数，以量化疾病的存在和进展；这些指数还应提供前所未有的药物功效评估。这个分两个阶段的快速通道提案计划以我们现有的小型队列研究作为更大规模队列研究的路线图：第一阶段为期六个月，使用我们现有的小型 16 AD 和 16 NEC 样本队列来： 目标 1. 研究可能向下miR-34a 已知靶标的调节；目标 2. 开展试点 miR-34a/SIRT1 TPR 指数的可行性研究；以及为期两年、包含 200 名更大队列的 II 期研究AD 和 200 名 NEC 参与者：目标 1. 建立 PBMC-DNA、RNA 和蛋白质样本以及血清/血浆样本的生物存储库，用于目标 2 和 3 中的测定；生成基于 PBMC 的 miR34a/SIRT1（和其他目标）TPR 指数；以及目标 3. 进行可行性研究以开发基于血清/血浆的 miR- 34a/SIRT1-TPR 指数。该项目的成功将使我们能够生成基于 PBMC 和血清的 miR-TPR 指数，作为 AD 受害者的个性化诊断，满足医疗保健的迫切需求，为疾病受害者及其护理人员带来巨大收益。 ，以及我们整个社会。 公共健康相关性：目前，阿尔茨海默病 (AD) 缺乏任何基于血液的诊断，需要患者忍受艰苦的神经心理学测试、侵入性脑脊液采集和/或昂贵的 MRI 或 PET 成像，最终诊断要推迟到我们的初步发现基于关于一种新型分子物种、microRNA (miR) 及其对其靶标表达的“拉锯”部分抑制的新科学。基因，表明AD的潜在疾病生物标志物可以在外周血单核细胞和/或血清/血浆中系统检测到，并且可以量化为miR-靶标对比率（TPR）。我们的计划是定义。 AD 特异性 TPR 指数，最初关注 miR-34a 及其靶标 SIRT1，已知 SIRT1 的减少与 Tau 和 A242（AD 的两个标志）的增加有关发病机制；我们的最终目标是 TPR 指数的“工具箱”，miR-34a/SIRT1-TPR 是第一个此类 AD 诊断，不仅表明疾病的存在，而且表明其进展（甚至药物疗效监测），对于这种代价高昂的疾病的受害者以及我们整个社会来说，这是一个巨大的战略收益！

项目成果

Increased microRNA-34c abundance in Alzheimer's disease circulating blood plasma.

阿尔茨海默病循环血浆中 microRNA-34c 丰度增加。

• 发表时间: 2014
• 作者: Bhatnagar, Shephali;Chertkow, Howard;Schipper, Hyman M;Yuan, Zongfei;Shetty, Vikranth;Jenkins, Samantha;Jones, Timothy;Wang, Eugenia
• 通讯作者: Wang, Eugenia