Circulating organ-enriched microRNAs as biomarkers of aging

富含循环器官的 microRNA 作为衰老生物标志物

• 批准号: 9139280
• 负责人: SAMUIL R UMANSKY
• 金额: $ 22.46万
• 依托单位: DIAMIR, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9139280
• 关键词: Age; Aged, 80 and over; Aging; Alzheimer' s Disease; Anus; Area; Behavior Therapy; Biological Assay; Biological Markers; Biological Sciences; Blood; Brain; Brain region; Cells; Centenarian; Cerebellum; Characteristics; Cognition; Cognitive; Data; Data Analyses; Detection; Development; Diagnostic; Diet; Disease; Early Diagnosis; Ethnic Origin; Evaluation; FRAP1 gene; Food Supplements; Functional disorder; Gender; Goals; Hippocampus (Brain); In Vitro; Inflammation; Inflammatory; Life; Life Style; Longevity; Lung; Malignant Neoplasms; Marketing; MicroRNAs; Midbrain structure; Molecular; Monitor; Natural Products; Neurites; Neurodegenerative Disorders; New York; Organ; Parabiosis; Parkinson Disease; Pathway interactions; Phase; Pituitary Gland; Plasma; Process; Race; Regimen; Risk Factors; Sampling; Sensitivity and Specificity; Small Business Innovation Research Grant; Smoking; Synapses; Technology; Testing; Therapeutic; Therapeutic Intervention; Validation; Women' s Group; Work; age difference; age group; age related; aging brain; anti aging; base; body system; brain health; candidate marker; circulating microRNA; clinical Diagnosis; commercial application; cost effective; gastrointestinal system; human disease; human old age (65+); innovation; knowledge base; men' s group; microRNA biomarkers; mild cognitive impairment; minimally invasive; molecular diagnostics; nervous system disorder; neuron loss; normal aging; phase 1 study; public health relevance; residence; software development; success

 DESCRIPTION (provided by applicant): A number of academic groups and life sciences companies are developing and testing approaches to delay aging -- the most significant risk factor for the vast majority of serious human diseases. Critical for these efforts is the development and validation of minimally invasive, cost-effective biomarkers of aging. DiamiR, a molecular diagnostics company, has developed proprietary platform technology for early detection and moni- toring of pathophysiological processes in different organs based on analysis of organ-enriched microRNA (miRNA) pairs in plasma. In this SBIR Phase I we propose to use the technology to select effective biomarkers of brain aging. Brain aging is characterized by neurite and synapse dysfunction and loss and neuronal death. A hypothesis being tested in the current proposal is that these processes can be detected in vitro by quantitative (RT-qPCR) analysis of brain-enriched and inflammation-associated miRNAs circulating in the blood. miRNAs enriched in different brain regions (hippocampus, midbrain, cerebellum, cortex, pituitary gland) and present in neurites and synapses, and several inflammation-associated miRNAs will be tested as biomarker candidates. Our previous studies on brain health produced highly promising results: biomarker miRNA pairs selected among brain-enriched miRNAs circulating in plasma were found to detect Mild Cognitive Impairment (MCI) with up to 96% accuracy, predict progression from normal cognition to MCI with 84% accuracy 1-5 years prior to clinical diagnosis, and differentiate Alzheimer's and Parkinson's diseases from age-matched control and from each other with accuracy >85%. In the preliminary study on aging several brain-enriched miRNAs were found to differentiate cognitively normal subjects of two age groups with p < 0.05 to p < 0.001. The current study will be performed using plasma samples prospectively collected at the New York Blood Center. Specific aims include (1) assessing feasibility of the approach and selecting miRNA biomarker pairs effectively differentiating younger (26-35 year-old) from older (56-65 year-old) healthy subjects (20 samples per group); and (2) using sets of miRNA biomarker pairs selected in Aim 1 to evaluate age-related dynamics and gender-dependent differences in plasma samples collected from 26 to 75 year-old healthy subjects (100 samples in total). In Phase II, DiamiR will assemble a knowledgebase by conducting studies with 1,000+ plasma samples collected from 20 to 90 year-old subjects. Further, miRNAs enriched in other than brain organs will be tested as biomarkers of aging of these organs. The generated data will be used to determine age-dependent ranges of concentrations of miRNA biomarker pairs defining normal aging. The long-term goal of the project is to develop sensitive, minimally invasive molecular assays for evaluation and monitoring of aging in the brain and other organs. The assays will be developed as in vitro diagnostics (IVD) and used for monitoring of aging, for assessment of therapeutic regimens and life style changes aimed at delaying (or reversing) normal aging, and for early detection of anomalies characteristic of aging associated diseases.

 一些学术团体和生命科学公司正在开发和测试延缓衰老的方法-这是绝大多数严重人类疾病的最重要风险因素。这些努力的关键是开发和验证微创，具有成本效益的衰老生物标志物。DiamiR是一家分子诊断公司，已开发出专有平台技术，用于基于对血浆中器官富集的microRNA（miRNA）对的分析来早期检测和监测不同器官中的病理生理过程。在SBIR第一阶段，我们建议使用该技术来选择有效的脑老化生物标志物。脑老化的特征是神经突和突触功能障碍、丧失和神经元死亡。在当前的提议中正在测试的一个假设是，这些过程可以通过定量（RT-qPCR）分析血液中循环的脑富集和炎症相关的miRNA在体外检测。在不同脑区域（海马、中脑、小脑、皮质、脑垂体）中富集并存在于神经突和突触中的miRNA，以及几种炎症相关的miRNA将作为生物标志物候选物进行测试。我们以前对大脑健康的研究产生了非常有希望的结果：发现在血浆中循环的脑富集的miRNA中选择的生物标志物miRNA对以高达96%的准确度检测轻度认知障碍（MCI），在临床诊断前1 - 5年以84%的准确度预测从正常认知到MCI的进展，并将阿尔茨海默病和帕金森病与年龄匹配的对照组区分开来，准确率> 85%。在关于衰老的初步研究中，发现几种脑富集的miRNA以p <0.05至p <0.001区分两个年龄组的认知正常受试者。本研究将使用在纽约血液中心前瞻性采集的血浆样本进行。具体目标包括（1）评估该方法的可行性并选择有效区分年轻人的miRNA生物标志物对。（26 - 35岁）（56 - 65岁）健康受试者（每组20个样本）;和（2）使用目标1中选择的miRNA生物标志物对的集合来评估年龄相关的动力学和性别-从26至75岁健康受试者采集的血浆样品（共100份样品）的依赖性差异。在第二阶段，DiamiR将通过对从20至90岁受试者中收集的1，000多份血浆样本进行研究来建立知识库。此外，在脑器官以外的器官中富集的miRNA将作为这些器官衰老的生物标志物进行测试。生成的数据将用于确定定义正常衰老的miRNA生物标志物对浓度的年龄依赖性范围。该项目的长期目标是开发敏感的、微创的分子检测方法，用于评估和监测大脑和其他器官的衰老。该检测将开发为体外诊断（IVD），用于监测衰老，评估旨在延迟（或逆转）正常衰老的治疗方案和生活方式变化，以及早期检测衰老相关疾病的异常特征。