Generating Blood-based Diagnosis for Alzheimer Disease

阿尔茨海默病的血液诊断

• 批准号: 7801565
• 负责人: EUGENIA WANG
• 金额: $ 10.7万
• 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 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7801565
• 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 Targeting; Genes; Genetic Transcription; Goals; Healthcare; 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; TP53 gene; Testing; Translations; Untranslated RNA; Up-Regulation; Work; amyloid precursor protein processing; base; cohort; cyclin E2; drug efficacy; feeding; foot; 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(申请人提供)：目前缺乏基于血液的诊断要求AD患者接受侵入性脊髓液(CSF)抽吸、昂贵的MRI或PET成像，或者艰难的心理测试，这些都不适合我们的老年人，而且成本也很高。战略上，我们将通过产生在外周单核细胞和血清/血浆中可检测到的系统生物标志物来解决这一未得到满足的需求，重点关注两类分子，微RNA及其靶基因，这两类分子通常表现出相反的关系，因为前者通过在信息的编码区或在3“非翻译区结合从而降解它或在3”非翻译区抑制翻译而部分抑制后者的“二聚体开关”表达。因此，关键的microRNAs及其靶标可以作为疾病的生物标志物，处于拉锯平衡状态，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组(NEC)进行的初步研究显示：1.AD患者PBMC中消息水平的基因表达明显下调；2.相同个体PBMC中microRNA(MiR)表达的相关上调。在这个提议中，我们关注一个特定的上调的microRNA，miR-34a，它的已知靶标是SIRT1，CDK4，CDK6，Cyclin E2，BCL2等。SIRT1是7个成员的沉默信息调节蛋白家族的成员。卡路里限制通过触发SIRT1的表达来延长寿命，SIRT1也可以被红酒多酚白藜芦醇模仿。SIRT1的减少与Tau和A242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患者PBMC和血清/血浆中可检测到一种全身性效应；上调miR-34a可能导致SIRT1表达下调，并伴随着病理生理结果。在这项提案中，我们计划对miR-34a/SIRT1目标配对比率(TPR)指数的变化进行拉锯战，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疗效评估。这两个阶段的快速通道建议是以我们现有的小型队列研究作为更大队列研究的路线图计划的：第一阶段为期六个月，我们现有的16个AD和16个NEC样本队列：目的1.研究下调miR-34a“S已知靶标的可能性；以及目标2.开展试点MIR-34a/SIRT1 TPR指数的可行性研究；以及第二阶段，200名AD和200名NEC参与者的较大队列：目标1.建立用于AIMS 2和3中的分析的PBMC DNA、RNA和蛋白质样本以及血清/血浆样本的生物储存库；目的2.生成基于PBMC的miR34a/SIRT1(和其他靶点)TPR指数；以及目的3.开展基于血清/血浆的miR-34a/SIRT1-TPR指数的可行性研究。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、他们的照顾者和整个社会带来巨大收益。 公共卫生相关性：目前，由于没有任何基于血液的阿尔茨海默病诊断方法，S病(AD)患者需要忍受艰巨的神经心理测试、侵入性脑脊液抽吸和/或昂贵的核磁共振或正电子发射计算机断层扫描，直到脑部尸检才能做出明确诊断。我们的初步发现基于一种新的分子物种microRNAs(MiR)及其对其靶基因(S)表达的拉锯法部分抑制，表明AD的潜在疾病生物标志物可在外周血单核细胞和/或血清/血浆中系统地检测到，并可能被定量为miR-靶基因对Ra-tios(TPR)。我们的计划是定义特定于AD的TPR指数，最初专注于miR-34a及其靶点SIRT1，已知其减少与Tau和A242的增加有关，这是AD发病的两个标志；我们的最终目标是TPR指数的“工具箱”，miR-34a/SIRT1-TPR是第一个这样的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和整个社会来说是一个巨大的战略收获！