AGING IN A HYPERLIPIDEMIC ENVIRONMENT

高脂血症环境中的衰老

• 批准号: 6287930
• 负责人: JIAN X ZHANG
• 金额: $ 6.5万
• 依托单位: UNIVERSITY OF NORTH CAROLINA CHARLOTTE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2002-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6287930
• 关键词: aging; caloric dietary content; disease /disorder etiology; fibrosis; genetically modified animals; hyperlipidemia; intravital microscopy; laboratory mouse; liver circulation; liver disorder; microcirculation; nutrition related tag

Hyperlipidemia, pandemic among aging individuals, is an established risk factor for heart disease. The development of liver disease in the aging human population is frequently accompanied by hyperlipidemia. A causal relationship between hyperlipidemia and liver damage has not been investigated. Furthermore, basic information concerning the effect of chronic hyperlipidemia on the aging liver is lacking. This pilot R03 proposal has as its primary focus to achieve a basic understanding of the influence of caloric restriction on the age related changes in liver function observed in hyperlipidemic mice as compared with normolipidemic littermates. This proposal builds on recent findings in our laboratory that show hyperlipidemic male and female mice develop prefibrotic liver disease by 8 - 10 months of age as compared with normal littermates or unrelated control mice. This study will use age and sex-matched normal and transgenic mice overexpressing apolipoprotein C-I that present with combined hyperlipidemia. Normal and hyperlipidemic transgenic mice at 5, 10 and 15 months maintained on ad libitum access to chow or on chronic energy intake restriction (40% reduction based on ad libitum consumption) will be investigated to determine changes in plasma lipids and lipoprotein levels. Intravital microscopy will be used to determine liver microvascular changes; and liver metabolic indicators will be monitored in each group to evaluate overall function. This project will provide fundamental, new information regarding age-related changes in the liver under normolipidemic and hyperlipidemic states. Understanding age-dependent attenuation in the liver has the potential to contribute to elucidating mechanisms in age-related alterations in systemic function, disease development, drug metabolism and susceptibility to acute stresses.

高脂血症在老年人中流行，是心脏病的既定危险因素。 老年人群中肝脏疾病的发展经常伴有高脂血症。 尚未研究高脂血症和肝损害之间的因果关系。 此外，缺乏关于慢性高脂血症对衰老肝脏影响的基本信息。 该试验性R 03提案的主要重点是基本了解热量限制对高脂血症小鼠与同窝出生的正常脂血症小鼠相比观察到的年龄相关肝功能变化的影响。 这一提议建立在我们实验室最近的发现基础上，该发现显示，与正常同窝小鼠或无关对照小鼠相比，高脂血症雄性和雌性小鼠在8 - 10个月龄时发生纤维化前肝病。 本研究将使用年龄和性别匹配的正常小鼠和过表达载脂蛋白C-I的转基因小鼠，这些小鼠存在混合型高脂血症。 将研究在5、10和15个月时维持自由进食或长期能量摄入限制（基于自由消耗减少40%）的正常和高脂血症转基因小鼠，以确定血浆脂质和脂蛋白水平的变化。 将使用活体显微镜检查确定肝脏微血管变化;并将监测各组的肝脏代谢指标，以评估整体功能。 该项目将提供关于正常血脂和高血脂状态下肝脏年龄相关变化的基本新信息。 了解肝脏中的年龄依赖性衰减有可能有助于阐明全身功能、疾病发展、药物代谢和急性应激敏感性中与年龄相关的改变机制。