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 遗传倾向的动物模型中动脉粥样硬化的进展 疾病的发展，渡边遗传性高脂血症兔 （WHHL）。研究发现，随着社会条件的稳定， 附属社会行为，减缓动脉粥样硬化病变的进展 在这些动物中。相比之下，处于不稳定社会条件下的动物， 表现出增加的竞争行为，单独饲养的动物表现出 显着的主动脉病变。这些数据不能完全解释 静息血浆糖皮质激素、性腺类固醇、脂质水平，也没有静息 心血管措施。据推测，慢性激活 交感神经系统（SNS）加速了疾病的进展 动脉粥样硬化。此外，我们还将检查中枢神经系统（CNS） SNS 和下丘脑垂体调节的潜在机制 肾上腺皮质轴 (HPA)，主要关注中枢的作用 促肾上腺皮质激素释放激素 (CRH) 和催产素 (OT) 控制 SNS 和 HPA 反应。据推测，CRH 在 压力行为会刺激 SNS 和 HPA，从而加速 疾病的进展。相比之下，中央 OT 与 增加亲和行为，可以在稳定的社交过程中缓冲有机体 通过抑制 HPA 轴和 SNS 来免受压力影响 活动。单独饲养的动物表现出低糖皮质激素水平 表现出很少的压力行为，但仍然发展出显着的 动脉粥样硬化。这些久坐的动物比其他动物体重增加更多 其他群体并出现严重的高胰岛素血症，这表明风险 与胰岛素代谢综合征相关的因素可能特别重要 对于该组疾病的进展很重要。拟议的工作 将： 1) 评估 SNS 在行为相关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 中枢 CRH 在调节 SNS 活性和动脉粥样硬化过程中的作用 通过集中管理的 CRH 拮抗剂造成慢性社会压力，3) 措施 下丘脑室旁核 OT 释放的变化 通过使用慢性微透析来调节社会环境的功能，4) 确定中枢 OT 在调节 HPA 和 SNS 活动中的作用， 及其通过集中管理的 OT 与动脉粥样硬化的关系 拮抗剂，5）评估饮食限制或日常锻炼对 与胰岛素代谢综合征和动脉粥样硬化相关的危险因素 在单独笼养的 WHHL 中，6）检查社会因素的影响 环境对杂合子 WHHL 动脉粥样硬化的影响，另一种模型 在很大程度上与血脂状况和疾病进展更密切相关 人类的百分比。