Stress, Cellular Aging and Susceptibility to Infectious Disease

压力、细胞衰老和传染病易感性

• 批准号: 7832621
• 负责人: SHELDON A COHEN
• 金额: $ 23.6万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7832621
• 关键词: Accounting; Acute; Address; Adult; Aging-Related Process; Anti-Inflammatory Agents; Anti-inflammatory; Antibody Formation; Antiviral Agents; Area; Biochemical; Biological; Biological Markers; Biological Markers; CD28 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Caregivers; Caring; Catecholamines; Cell Aging; Cell Death; Cell division; Cell physiology; Child; Chromosomes; Chronic; Chronic stress; Chronically Ill; Clinical; Common Cold; Communicable Diseases; Coronavirus; Data; Development; Disease; Disease susceptibility; Elderly; Enzymes; Goals; Health; Hormones; Host resistance; Human; Hydrocortisone; Immune; Immunocompetence; Immunologics; Infection; Infectious Agent; Isoprostanes; Laboratories; Lead; Length; Leukocytes; Life Stress; Link; Lymphocyte; Lymphocyte Subset; Malignant Neoplasms; Measures; Mediating; Monitor; Nose; Oxidative Stress; Parents; Pathway interactions; Peripheral Blood Mononuclear Cell; Physiological; Play; Poverty; Predisposition; Production; Psyche structure; Psychological Stress; Psychoneuroimmunology; Quarantine; Questionnaires; Reporting; Resistance; Resistance to infection; Respiratory syncytial virus; Rhinovirus; Risk; Role; Series; Stress; T-Lymphocyte; Telomerase; Telomere Shortening; Testing; Unemployment; Vaccines; Validation; Viral; Virus; Woman; Work; aged; cytokine; effective intervention; experience; fighting; healthy volunteer; human subject; immune function; influenzavirus; interest; mortality; novel marker; psychologic; public health relevance; research study; respiratory; response; safety testing; senescence; social; stressor; telomere

DESCRIPTION (provided by applicant): This application addressed Broad Challenge Area: (03) Biomarker Discovery and Validation and specific challenge topic: 03-AT-101* Psychoneuroimmunology biomarkers of stress. Identification of biomarkers to assess the impact of stress, both social and biological, on immune function. The rate of cell senescence in lymphocytes (particularly in CD8 cells), as indicated by decreases in telomere length, may be an important new marker of immunocompetence and, in turn, host resistance to infectious agents. Loss of telomere length may be especially important in understanding the role of psychological stress in infectious illness. Stress is associated with greater susceptibility to upper respiratory viral illnesses. In addition, increases in psychological stress are associated with shorter telomere length in lymphocytes. This evidence suggests that stress may influence disease susceptibility via its effects on lymphocyte cell senescence. Moreover, psychological stress has also been associated with greater oxidative stress and less telomerase activity. Both of these contribute to shortening of telomeres, suggesting that psychological stress may shorten telomeres via its effects on these telomere regulators. We have a unique opportunity to address these hypotheses in healthy adult human subjects by adding assessments of oxidative stress, telomerase activity and telomere length at baseline to an ongoing viral- challenge study. Baseline measures in the parent study include a range of stress measures: psychological and social measures of stress by questionnaire, assessments of basal diurnal cortisol rhythms over three days and of autonomic and cortisol response to an experimental stressor in the laboratory. After completing all baseline measures, subjects are exposed to a safety tested rhinovirus and monitored in quarantine for the development of infection and illness. Local (nasal secretory) release of pro- and anti- inflammatory cytokines are also assessed after viral exposure. Approximately 40% of the subjects develop a clinical illness in response to the viral challenge. In this extension of that study, we propose to evaluate whether telomere length predicts susceptibility to infection and disease expression and whether it constitutes a mediating pathway through which stress influences resistance to infectious disease. We can also determine whether or not telomere length mediates the known effects of psychological stress on the locally produced pro- and anti-inflammatory cytokines that play a role in illness expression. Finally, we can test whether or not telomerase activity and oxidative stress constitute pathways through which psychological, social and biological markers of stress might influence telomere length. This work has implications for understanding the role of stress in the aging process and particularly important implications for reducing disease in the elderly and those experiencing long-term stress (e.g. the chronically unemployed, caregivers, and those suffering from poverty). PUBLIC HEALTH RELEVANCE: A major focus of the project is to determine whether immune cell senescence (as assessed by telomere length) plays an important role in our ability to fight off infection. Because life stress has been found to be associated with greater senescence, we are also testing whether stress-associated increases in senescence can account for why life stress increases our risk for infectious diseases. An in-depth understanding of the role how stress influences our health can help lead to effective interventions to protect people at risk.

描述（由申请人提供）：本申请涉及广泛挑战领域：（03）生物标志物发现和验证和特定挑战主题：03-AT-101* 压力的心理神经免疫学生物标志物。鉴定生物标志物以评估社会和生物压力对免疫功能的影响。淋巴细胞（特别是CD 8细胞）中细胞衰老的速率，如端粒长度的减少所示，可能是免疫活性的重要新标志，进而是宿主对感染因子的抗性。端粒长度的丧失对于了解心理压力在传染病中的作用可能特别重要。压力与上呼吸道病毒性疾病的易感性有关。此外，心理压力的增加与淋巴细胞端粒长度的缩短有关。这一证据表明，压力可能会影响疾病的易感性，通过其对淋巴细胞衰老的影响。此外，心理压力也与更大的氧化应激和更少的端粒酶活性有关。这两个因素都有助于缩短端粒，表明心理压力可能通过影响这些端粒调节因子来缩短端粒。我们有一个独特的机会来解决这些假设在健康的成年人受试者，增加评估的氧化应激，端粒酶活性和端粒长度在基线正在进行的病毒攻击研究。父母研究中的基线测量包括一系列压力测量：通过问卷调查进行的压力的心理和社会测量，三天内基础昼夜皮质醇节律的评估以及实验室中对实验性压力源的自主神经和皮质醇反应。在完成所有基线测量后，将受试者暴露于安全性测试的鼻病毒，并在隔离中监测感染和疾病的发展。在病毒暴露后还评估促炎性和抗炎性细胞因子的局部（鼻分泌）释放。约40%的受试者在病毒攻毒后发生临床疾病。在该研究的扩展中，我们建议评估端粒长度是否预测对感染和疾病表达的易感性，以及它是否构成压力影响对感染性疾病抵抗力的介导途径。我们还可以确定端粒长度是否介导心理压力对局部产生的促炎和抗炎细胞因子的已知影响，这些细胞因子在疾病表达中发挥作用。最后，我们可以测试端粒酶活性和氧化应激是否构成压力的心理，社会和生物标志物可能影响端粒长度的途径。这项工作对理解压力在衰老过程中的作用具有重要意义，对减少老年人和长期承受压力的人（例如长期失业者，照顾者和贫困者）的疾病具有特别重要的意义。 公共卫生相关性：该项目的一个主要重点是确定免疫细胞衰老（通过端粒长度评估）是否在我们抵抗感染的能力中发挥重要作用。由于生活压力与更大的衰老有关，我们也在测试与压力相关的衰老增加是否可以解释为什么生活压力会增加我们患传染病的风险。深入了解压力如何影响我们的健康，有助于采取有效的干预措施，保护处于危险中的人。