Neural and Molecular Mechanisms Underlying Stress-Induced Inflammatory Responses

压力诱发炎症反应的神经和分子机制

• 批准号: 10185562
• 负责人: Keely Ann Muscatell
• 金额: $ 62.19万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10185562
• 关键词: Acute; Adrenergic Agents; Adrenergic beta-Antagonists; Affective; American; Amygdaloid structure; Anterior; Atherosclerosis; Biological; Biological Assay; Blood specimen; Brain; Brain region; Cardiac; Cardiovascular Diseases; Cessation of life; Clinical Trials; Computing Methodologies; Data; Development; Dose; Double-Blind Method; Drug usage; Economic Burden; Etiology; Event; Functional Magnetic Resonance Imaging; Future; Gene Expression; Goals; Graph; Human; Inflammation; Inflammatory; Inflammatory Response; Insula of Reil; Interleukin-6; Intervention; Knowledge; Lead; Light; Link; Machine Learning; Maps; Mathematics; Measures; Medial; Mediating; Mediator of activation protein; Molecular; Network-based; Outcome; Pathology; Pathway Analysis; Pathway interactions; Pattern; Pattern Recognition; Pharmacology; Placebos; Play; Procedures; Propranolol; Proteins; Psychological Stress; Psychoneuroimmunology; Randomized; Research; Risk; Risk Factors; Role; Scanning; Shapes; Signal Pathway; Signal Transduction; Stress; Techniques; Testing; Time; Up-Regulation; Work; analytical tool; attenuation; beta-adrenergic receptor; cardiovascular disorder risk; computational neuroscience; cytokine; double-blind placebo controlled trial; economic cost; economic impact; health economics; inflammatory marker; innovation; neural circuit; neural patterning; neuroimaging; neuromechanism; novel; preclinical study; prevent; relating to nervous system; response; social; social genomics; stress reactivity; stressor; tool

PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) is the number one killer of Americans, and also causes significant economic costs to the nation. Thus, understanding the mechanisms through which CVD develops is of paramount importance if we are to successfully identify those at risk for CVD, and intervene to ultimately prevent CVD-related death and economic impact. Psychological stress reactivity has long been appreciated as a risk factor for negative CVD- related outcomes, and recent work suggests that inflammatory reactivity to stress is a critical biological mechanism through which stress increases risk for CVD. However, there are significant gaps in our current knowledge regarding the neural predictors and molecular pathways through which stress leads to inflammation. These knowledge gaps are critical to fill if we are to develop a full mechanistic understanding of how stress leads to CVD risk, and may also shed light on future intervention targets. Thus, the present project will use cutting- edge computational methods to identify neural signatures of stress-related inflammatory reactivity, and will use pharmacological tools to block an important stress-signaling pathway (i.e., beta-adrenergic signaling) and examine its effects on neural and inflammatory reactivity to stress. Study 1 (N=100) will use fMRI to examine neural responses to a social evaluative stress task, with blood samples taken before and after the stressor assayed for pro-inflammatory gene expression and circulating inflammatory proteins. We will use innovative multivariate machine learning analytic techniques to identify the neural patterns that predict changes in inflammation, as well as network-based analytic tools from mathematics to examine how large-scale brain networks change configuration in response to stress in ways that are linked to inflammation. In Study 2 (N=120), we will conduct a mechanistic, randomized, double-blind, placebo-controlled trial of the beta-adrenergic receptor blocker propranolol to examine how blocking beta-adrenergic signaling impacts neural and inflammatory responses to the social evaluative stress task. Together, these two studies will allow us to establish the neural signatures of stress-induced increases in inflammation (Aim 1), determine the effects of beta-adrenergic signaling on neural responses to stress (Aim 2), and examine the neural mediators of beta-adrenergic related attenuations in stress-related inflammatory reactivity (Aim 3). In doing so, this project will ultimately help identify neural signatures of risk for stress-related inflammation, as well as novel targets for future intervention to ameliorate the impact of stress on the brain and body and reduce the health and economic burden of CVD.

项目总结/文摘