Molecular interception and immunological characterization of age-associated disease

年龄相关疾病的分子拦截和免疫学表征

• 批准号: 10190562
• 负责人: Mark Morris Davis
• 金额: $ 63.87万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10190562
• 关键词: Adult; Affect; Age; Aging; Arterial Fatty Streak; Atherosclerosis; Automobile Driving; Biological Assay; Biological Clocks; Biological Markers; Biological Process; Buffers; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Chronic; Chronic Disease; Chronology; Clinical; DNA Methylation; DNA copy number; Data; Databases; Deposition; Deterioration; Developed Countries; Development; Diabetes Mellitus; Dimensions; Disease; Disease Clusterings; Early Intervention; Early treatment; Economic Burden; Elderly; Enrollment; Environment; Environmental Risk Factor; Event; Gene Expression; Gene Expression Profile; Genetic; Goals; Harvest; Health; Heart Transplantation; Immune; Immune system; Immunologic Monitoring; Immunologics; In Vitro; Individual; Inflammation; Intercept; Length; Life Style; Link; Longevity; Malignant Neoplasms; Maps; Mitochondrial DNA; Molecular; Monitor; Myocardial Infarction; Organ; Patient Care; Patient Monitoring; Patients; Phenotype; Physiological; Physiology; Play; Predisposition; Prognosis; Prognostic Marker; Resolution; Risk; Risk Factors; Role; Severities; Stroke; Surveys; Survivors; T-Lymphocyte; Testing; Twin Multiple Birth; Woman; Women' s Health; Work; active lifestyle; aged; atherosclerosis risk; base; clinical phenotype; cohort; comorbidity; cost estimate; design; disorder risk; experimental study; flu; frailty; genetic signature; healthy lifestyle; high dimensionality; immune function; indexing; insight; metabolomics; middle age; modifiable risk; non-invasive imaging; older patient; personalized medicine; prevent; recruit; respiratory; response; sedentary lifestyle; telomere; treatment response; treatment strategy

PROJECT SUMMARY In developed countries, noncommunicable diseases such as cancer, cardiovascular disease, chronic respiratory illness, and diabetes account for the majority of deaths among people aged 70 and older. The global economic burden to care for patients with noncommunicable diseases is astronomical. In 2010, it cost an estimated 47 trillion dollars in 2010-2030, which is equivalent to 75% of global gross domestic product in 2010, to provide care for patients with chronic disease. Clearly, we need a better strategy to identify patients at greatest risk so that we can prevent disease development or provide earlier intervention. Our recent work has suggested that a decline in immune function is a major, potentially modifiable, risk factor for the development of cardiovascular disease. It remains unclear, however, at what point in the patient’s lifespan does the immune system age and contribute to disease, how genetic and environmental factors affect immune age, and whether decline in immune function is also associated with the development of other noncommunicable diseases associated with chronological aging. Project 2 is designed to understand the relationship between immune-aging (whose deepened understanding and relationship to flu response we assess in Project 1) and the development of diseases associated with chronological aging - an association that we hypothesize begins in middle-age but extends throughout the individual’s life span. In Project 2, first, we add a middle age cohort of twins (MAT-SELA) demographically similar to the SELA cohort, to not only expand the age range of patients to be profiled, but also to disentangle the effects of genetics and the environment to immune aging. To further isolate the environmental effects on immune age, we will also compare the immune age of a super fit older cohort (AL-SELA) with that of the SELA cohort, who are normal, older patients leading sedentary lifestyles. Second, we perform an in-depth analysis of how immune age affects the development of cardiovascular disease, building from our previous work, by serially profiling the immune age of patients who are at greatest risk for developing atherosclerosis (e.g., plaque build-up, heart attack or stroke), monitoring these patients by non-invasive imaging for the development and/or progression of cardiovascular disease, and documenting any major adverse clinical events. Furthermore, we apply advanced immune-based assays developed by our lab to interrogate the molecular and cellular components of the atherosclerotic plaque, extending our recent finding that flu specific T cells are found in the atherosclerotic plaque, in order to better understand the underlying mechanisms behind recent clinical observations that having the flu increases the risk of heart attack and stroke. Lastly, we will determine if immune age contributes to other non-communicable diseases by comparing the immune gene signatures associated with advanced aging in our cohorts with publicly available databases to associate the immune state with disease likelihood, severity, and prognosis.

项目概要 在发达国家，癌症、心血管疾病、慢性呼吸道疾病等非传染性疾病 疾病和糖尿病是 70 岁及以上人群死亡的主要原因。全球经济 照顾非传染性疾病患者的负担是天文数字。 2010 年，估计花费了 47 2010-2030年将投入万亿美元，相当于2010年全球国内生产总值的75%，用于提供护理服务 对于慢性病患者。显然，我们需要更好的策略来识别风险最大的患者，以便 我们可以预防疾病的发展或提供早期干预。我们最近的工作表明 免疫功能下降是心血管疾病发生的一个主要的、潜在可改变的危险因素 疾病。然而，目前尚不清楚患者的免疫系统在生命的哪个阶段会老化并发生变化。 导致疾病的因素、遗传和环境因素如何影响免疫年龄以及免疫能力是否下降 功能也与其他非传染性疾病的发生有关 按时间顺序老化。项目 2 旨在了解免疫衰老之间的关系（其 加深了对我们在项目 1) 中评估的流感反应的理解和关系，以及 与时间老化相关的疾病——我们假设这种关联始于中年，但 延伸到个人的一生。在项目 2 中，首先，我们添加了一组中年双胞胎 (MAT-SELA) 在人口统计学上与 SELA 队列相似，不仅扩大了要分析的患者的年龄范围，而且 阐明遗传和环境对免疫衰老的影响。进一步隔离环境 对免疫年龄的影响，我们还将比较超级健康老年人群 (AL-SELA) 的免疫年龄与 SELA 队列是正常的老年患者，过着久坐的生活方式。其次，我们进行了深入的 根据我们之前的工作，分析免疫年龄如何影响心血管疾病的发展， 通过连续分析最有可能发生动脉粥样硬化的患者的免疫年龄（例如， 斑块积聚、心脏病发作或中风），通过非侵入性成像监测这些患者的发展 和/或心血管疾病的进展，并记录任何重大不良临床事件。此外， 我们应用我们实验室开发的先进的基于免疫的测定来询问分子和细胞 动脉粥样硬化斑块的成分，扩展了我们最近的发现，即流感特异性 T 细胞存在于动脉粥样硬化斑块中 动脉粥样硬化斑块，以便更好地了解近期临床背后的潜在机制 观察发现，流感会增加心脏病发作和中风的风险。最后，我们将确定是否免疫 通过比较与年龄相关的免疫基因特征，年龄有助于其他非传染性疾病 通过公开数据库将免疫状态与疾病联系起来，我们的队列中的晚期衰老 可能性、严重性和预后。