ENVIRONMENT, CNS, AND ATHEROSCLEROSIS IN AN ANIMAL MODEL

描述（由申请人提供）： 我们已经证明，社会行为因素可以影响 动脉粥样硬化在动物模型中的进展 渡边遗传性高脂血症兔 （WHHL）。人们发现，稳定的社会条件，伴随着增加 亲和的社会行为，减缓动脉粥样硬化病变的进展 在这些动物中。相反，处于不稳定社会环境中的动物， 表现出增加的激动行为，单独圈养的动物表现出 严重主动脉病变。这些数据不能完全用 静息血浆糖皮质激素、性腺类固醇、脂质水平，也不静息 心血管检查据推测，慢性激活的 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机制 肾上腺皮质轴（HPA），主要集中在中央的作用， 促肾上腺皮质激素释放激素（CRH）和催产素（OT）在SNS控制中的作用 HPA的反应。据推测，CRH，集中释放期间 压力行为，刺激SNS和HPA，从而加速 疾病的进展。与此相反，中央OT，这已被链接到 增加亲和行为，可能会缓冲有机体在稳定的社会 通过抑制HPA轴和SNS的应力的影响条件 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，但仍然发展显著 动脉粥样硬化这些久坐不动的动物体重增加得比 其他组和发展严重的高胰岛素血症，这表明， 与胰岛素代谢综合征相关的因素可能特别 对这一群体的疾病进展很重要。拟议工作 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中的作用 慢性社会压力通过中央管理的CRH拮抗剂，3）措施 下丘脑室旁核OT释放的变化， 通过使用慢性微透析，社会环境的功能，4） 确定中枢OT在HPA和SNS活性调节中的作用， 及其通过中枢给药OT与动脉粥样硬化的关系 拮抗剂，5）评估饮食限制或每日运动对 与胰岛素代谢综合征和动脉粥样硬化相关的危险因素， 在单独的笼子里，6）检查社会的影响， 环境对杂合子WHHL动脉粥样硬化的影响，一种替代模型 这与大部分人的血脂状态和疾病进展更为相似， 人类的百分比。

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.