Viral burden and systemic inflammation as biomarkers for chronic disease and frailty in aging

病毒负荷和全身炎症作为慢性疾病和衰老衰弱的生物标志物

基本信息

批准号：
10153615
负责人：
JANKO Z. NIKOLICH
金额：
$ 65.25万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10153615
关键词：
21 year old Activities of Daily Living Address Adult Age Age-Years Aging Antibody Response Arizona Bacteriophages Biological Markers Blood Blood Cells Blood Circulation Budgets Cardiovascular Diseases Caring Censuses Chronic Chronic Disease Clinical Clinical Research Consumption Cytokine Gene Cytomegalovirus DNA Viruses Data Detection Development Disease Doctor of Philosophy Elderly Etiology Exhibits Flow Cytometry Funding Gene Expression Profiling Genes Genetic Transcription Guidelines Health Care Costs Healthcare Immune Immune response Immune system Immunity Immunization Immunology Indiana Inflammation Inflammation Mediators Inflammatory Intervention Lead Link Lymphocyte Activation Malignant Neoplasms Measurement Measures Mediator of activation protein Medicare Metabolic Diseases Molecular Monitor Neurodegenerative Disorders Organism Outcome Peripheral Blood Mononuclear Cell Plasma Population Prospective cohort Proteins Public Health Questionnaires RNA Viruses Research Resources Sampling Shotgun Sequencing Source T-Cell Activation T-Lymphocyte Testing Universities Validation Viral Viral Load result Virus Virus Diseases Virus Latency acute infection age related aging population biomarker panel chronic infection cohort differential expression disorder risk frailty gastrointestinal immune activation immunosenescence member reactivation from latency recruit senescence systemic inflammatory response transcriptome sequencing virology virome young adult

项目摘要

Abstract According to the US Census Bureau there were 47.8 million people older than 65 living in the U.S. in 2015 and is projected to more than double by 2050. The implications on health care costs are substantial. Identifying members of the aging population at increased risk for disease and frailty is a major public health imperative. Frailty and many of the chronic diseases of aging coincide with chronic inflammation. The cause of chronic inflammation is not known. One potential etiology is lifelong stimulation of the immune system by acute and chronic infections. Chronic antigenic stimulation can lead to a state of “immunosenescence”, which is associated with chronic secretion of inflammatory mediators. Persistent viruses, by virtue of their ability to establish latency, are ideally poised to drive chronic antigenic stimulation. In this project we hypothesize that older adults will exhibit higher viral burden that will lead to increased immune stimulation and chronic inflammation, and that this burden will be able to predict propensity for and timing of frailty and age- related diseases. To address this hypothesis we will measure viral burden in the blood and link it to inflammatory gene expression profiling and markers of T cell activation/senescence to validate these as "biomarkers" for prediction of chronic disease and frailty. This will be done through two large aging cohorts which are collecting blood along with extensive questionnaires and tests to assess the presence of chronic diseases and frailty. We propose the following specific aims: (1) To measure the blood virome (including bacteriophages) in an elderly population and younger controls. We will determine the presence of RNA and DNA viruses as well as bacteriophages in the blood compartment of younger and older adults using shotgun sequencing and RNA-Seq. The presence and activity of cytomegalovirus as a potential driver of immune aging will be assessed by monitoring anti-CMV immune responses. (2) To assess markers of chronic inflammation in an elderly population and younger controls and correlate these with evidence of immune aging and viral specific immune responses. We will determine the degree of systemic inflammation in the blood of subjects through measurement of cytokines and gene expression profiling of PBMCs. We will assess the degree of lymphocyte activation, senescence, and virus-specific activity by flow cytometry. (3) To correlate the blood virome, evidence of systemic inflammation and the presence of chronic disease and frailty in test subjects and create a potential inflammatory and viral “biomarker” for the detection of the complications of aging. Using data from specific aims 1 and 2, we will connect viral burden (including bacteriophages) and markers of chronic inflammation to each other and to clinical outcomes in a cross-sectional and mixed cross-sectional/longitudinal manner. This interdisciplinary project should not only deliver biomarkers for the complications of aging, but also suggest potential interventions that might mitigate the development of chronic disease and frailty in the aging population.

抽象的根据美国人口普查局的数据，2017 年美国 65 岁以上人口为 4780 万人。预计到 2015 年将增加一倍以上。这对医疗保健费用的影响是巨大的。识别老龄化人口中疾病和虚弱风险增加的成员是一项重要的公共卫生问题衰弱和许多慢性衰老疾病都与慢性炎症有关。慢性炎症的一种潜在病因尚不清楚。急性和慢性感染。慢性抗原刺激可导致“免疫衰老”状态。与炎症介质的慢性分泌有关，因为它们有能力。建立潜伏期，理想地准备驱动慢性抗原刺激。老年人将表现出更高的病毒负荷，这将导致免疫刺激增加和慢性病炎症，并且这种负担将能够预测虚弱和年龄的倾向和时间- 为了解决这一假设，我们将测量血液中的病毒负荷并将其与相关疾病联系起来。炎症基因表达谱和 T 细胞激活/衰老标记，以验证这些用于预测慢性疾病和虚弱的“生物标志物”这将通过两个大型老龄化队列来完成。他们广泛收集血液并进行问卷调查和测试，以评估是否存在慢性病我们提出以下具体目标：（1）测量血液病毒组（包括）。噬菌体）在老年人群和年轻对照中我们将确定 RNA 的存在。和 DNA 病毒以及年轻人和老年人血液室中的噬菌体鸟枪法测序和 RNA 测序巨细胞病毒的存在和活性作为潜在的驱动因素通过监测抗 CMV 免疫反应来评估免疫衰老 (2) 评估标记物。老年人群和年轻对照组的慢性炎症并将其与证据相关联我们将确定免疫老化和病毒特异性免疫反应的程度。通过测量细胞因子和基因表达谱来了解受试者血液中的炎症我们将通过流式评估淋巴细胞活化、衰老和病毒特异性活性的程度。 (3) 将血液病毒组、全身炎症的证据和存在的情况联系起来。测试对象的慢性疾病和虚弱，并创建潜在的炎症和病毒“生物标志物” 为了检测衰老并发症，我们将使用特定目标 1 和 2 的数据连接病毒。慢性炎症的负担（包括噬菌体）和标志物之间以及临床结果的关系以横截面和混合横截面/纵向的方式这个跨学科项目不应该。不仅提供衰老并发症的生物标志物，而且还提出可能的潜在干预措施减轻老年人口中慢性疾病和虚弱的发展。