ENVIRONMENT, CNS, AND ATHEROSCLEROSIS IN AN ANIMAL MODEL

动物模型中的环境、中枢神经系统和动脉粥样硬化

• 批准号: 6921960
• 负责人: PHILIP M MCCABE
• 金额: $ 21.29万
• 依托单位: UNIVERSITY OF MIAMI CORAL GABLES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6921960
• 关键词: antiadrenergic agents; atherosclerosis; behavioral /social science research tag; behavioral medicine; body physical activity; brain electrical activity; corticotropin releasing factor; disease /disorder model; environmental stressor; ethology; gene environment interaction; hormone regulation /control mechanism; hypothalamic pituitary adrenal axis; hypothalamus; laboratory rabbit; metabolic syndrome; model design /development; neuroendocrine system; oxytocin; physiologic stressor; psychological stressor; psychophysiology; social adjustment; social behavior; socioenvironment; sympathetic nervous system

DESCRIPTION (provided by applicant): We have demonstrated that social behavioral factors can influence the progression of atherosclerosis in an animal model genetically predisposed to the development of disease, the Watanabe Heritable Hyperlipidemic Rabbit (WHHL). It was found that stable social conditions, accompanied by increased affiliative social behavior, slowed the progression of atherosclerotic lesions in these animals. In contrast, animals in unstable social conditions, displaying increased agonistic behavior, and animals housed singly exhibited significant aortic pathology. These data could not be explained entirely by resting plasma glucocorticoids, gonadal steroids, lipid levels, nor resting cardiovascular measures. It is hypothesized that chronic activation of the sympathetic nervous system (SNS) accelerates the progression of atherosclerosis. In addition, we will examine Central Nervous System (CNS) mechanisms underlying the regulation of the SNS and hypothalamic pituitary adrenocortical axis (HPA), focusing primarily on the roles of central corticotropin-releasing hormone (CRH) and oxytocin (OT) in the control of SNS and HPA responses. It is hypothesized that CRH, released centrally during stressful behavior, stimulates the SNS and HPA, thereby accelerating the progression of disease. In contrast, central OT, which has been linked to increased affiliative behavior, may buffer the organism during stable social conditions from the effects of stress by inhibiting the HPA axis and SNS activity. Animals housed singly exhibited low glucocorticoid levels and showed little stressful behavior, yet still developed significant atherosclerosis. These sedentary animals gained more body weight than the other groups and developed profound hyperinsulinemia, suggesting that risk factors related to the Insulin Metabolic Syndrome may be particularly important for the progression of disease in this group. The proposed work will: 1) assess the role of the SNS in behaviorally-related atherosclerosis via selective adrenergic receptor antagonists, 2) determine the role of central CRH in the regulation of SNS activity and atherosclerosis during chronic social stress via a centrally administered CRH antagonist, 3) measure changes in the release of OT in the hypothalamic paraventricular nucleus as a function of social environment through the use of chronic microdialysis, 4) determine the role of central OT in the regulation of HPA and SNS activity, and its relationship to atherosclerosis via a centrally administered OT antagonist, 5) assess the impact of dietary restriction or daily exercise on risk factors related to the insulin metabolic syndrome and atherosclerosis and in individually-caged WHHLs, and 6) examine the influence of social environment on atherosclerosis in the heterozygous WHHL, an alternative model that more closely parallels lipid status and disease progression in a large percentage of humans.

描述（由申请人提供）： 我们已经证明，社会行为因素可以影响 动物模型中动脉粥样硬化的进展在遗传上易于 疾病的发展，渡边可遗传的高脂兔 （whhl）。发现稳定的社会条件伴随着增加 隶属性社会行为，减慢了动脉粥样硬化病变的进展 在这些动物中。相反，在不稳定的社会条件下的动物， 表现出更大的激动性行为，并且单独展示的动物表现出 重要的主动脉病理。这些数据无法完全解释 静止的血浆糖皮质激素，性腺类固醇，脂质水平，也不静止 心血管措施。假设慢性激活 交感神经系统（SNS）加速了 动脉粥样硬化。此外，我们将检查中枢神经系统（CNS） SNS和下丘脑垂体调节的基础机制 肾上腺皮质轴（HPA），主要关注中央的角色 在SNS控制中，促肾上腺素释放激素（CRH）和催产素（OT） 和HPA响应。假设CRH在中心发行 压力性行为，刺激SNS和HPA，从而加速了 疾病的进展。相比之下，已与 增加的隶属行为，可能会在稳定的社会中缓冲生物体 通过抑制HPA轴和SNS的压力影响的条件 活动。单独饲养的动物表现出低糖皮质激素水平和 表现出很少的压力行为，但仍然发展出很大的意义 动脉粥样硬化。这些久坐的动物比 其他群体并发展出深远的高胰岛素血症，表明风险 与胰岛素代谢综合征有关的因素可能特别是 对于这一组疾病的进展至关重要。拟议的工作 威尔：1）评估SN在行为相关的动脉粥样硬化中的作用 通过选择性肾上腺素能受体拮抗剂，2）确定 在调节SNS活性和动脉粥样硬化期间的中央CRH 通过中央管理的CRH拮抗剂的慢性社会压力，3）措施 下丘脑旁腔核中OT释放的变化作为A 通过使用慢性微透析，社会环境的功能，4） 确定中心OT在调节HPA和SNS活性中的作用， 及其与动脉粥样硬化的关系通过中央施用的OT 对手，5）评估饮食限制或日常运动对 与胰岛素代谢综合征和动脉粥样硬化以及 在单独割伤的WHHL中，6）检查社会的影响 杂合WHHL中动脉粥样硬化的环境，一种替代模型 在大的 人类的百分比。