Generating Blood-based Diagnosis for Alzheimer Disease

阿尔茨海默病的血液诊断

• 批准号: 8134131
• 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 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8134131
• 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）穿刺，昂贵的MRI或PET成像，或艰苦的心理测试，所有这些对我们的老年人来说都是不合适和昂贵的。从战略上讲，我们将通过产生在外周单核细胞（PBMC）和血清/血浆中可检测的系统性生物标志物来解决这一未满足的需求，重点是两类分子，微RNA及其靶基因，它们通常表现出相反的关系，因为前者的非编码RNA通过结合在信息的编码区，从而使其降解，或在3 ″-非翻译区降解，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“跷跷板”平衡中，适用于新的诊断和/或治疗。我们对16名AD患者和16名年龄匹配的正常老年对照（NEC）进行了一项小型队列的初步研究，结果显示：1。在AD PBMC中在信息水平上基因表达的主要下调;和2.相同个体PBMC中microRNA（miR）表达的相关上调。在本研究中，我们重点研究了一种特异性上调的microRNA，miR-34 a，其已知的靶点是SIRT 1，cdk 4，cdk 6，cyclin E2，bcl 2等。SIRT 1是7成员沉默信息调节蛋白家族的一员。热量限制通过触发SIRT 1的表达来延长寿命，SIRT 1也可以被白藜芦醇（一种红葡萄酒多酚）模仿。SIRT 1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，在PBMC和血清/血浆中存在可检测到的全身效应;上调的miR-34 a可能诱导SIRT 1下调，伴随病理生理结果。在这项提案中，我们计划为这种变化的“跷跷板”生成miR-34 a/SIRT 1靶对比（TPR）指数，以量化疾病的存在和进展;这些指数还应该提供前所未有的药物疗效评估。该快速通道方案计划分为两个阶段，以我们现有的小型队列研究作为更大队列研究的路线图：第一阶段为期6个月，采用我们现有的16个AD和16个NEC小型样本队列，目的是：目标1。研究miR-34 a已知靶点的可能下调;和Aim 2.开发试验性miR-34 a/SIRT 1 TPR-指数的可行性研究;以及具有200名AD和200名NEC参与者的较大群组的两年II期：目标1.建立PBMC-DNA、-RNA和-蛋白质样本以及血清/血浆样本的生物储存库，用于目标2和3中的测定;目标2。生成基于PBMC的miR 34 a/SIRT 1（和其他靶标）TPR指数;和Aim 3.进行可行性研究以开发基于血清/血浆的miR-34 a/SIRT 1-TPR指标。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患者的个性化诊断，满足医疗保健的迫切需求，为疾病患者，他们的护理人员和我们的社会带来巨大的收益。 公共卫生关系：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，侵入性脑脊液穿刺和/或昂贵的MRI或PET成像，最终诊断推迟到脑尸检。我们的初步发现基于关于新分子种类microRNA（miR）及其靶基因表达的“跷跷板”部分抑制的新科学，表明AD的潜在疾病生物标志物在外周血单核细胞和/或血清/血浆中可全身检测，并且可定量为miR-靶对Ra（TPR）。我们的计划是定义AD特异性TPR指数，最初重点关注miR-34 a及其靶点SIRT 1，已知其减少与Tau和A242增加有关，这是AD病因的两个标志;我们的最终目标是TPR指标的“工具箱”，miR-34 a/SIRT 1-TPR是第一个这样的AD诊断，不仅指示疾病的存在，而且它的进展（甚至是药物疗效监测），这对这种代价高昂的疾病的受害者和我们整个社会来说都是一个巨大的战略收益！