Does UCP2/3 Overexpression Mimic Caloric Restriction?

UCP2/3 过度表达是否模仿热量限制？

• 批准号: 6533948
• 负责人: BARBARA Ann HORWITZ
• 金额: $ 42.6万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6533948
• 关键词: apoptosis; bioenergetics; blood glucose; caloric dietary content; dietary restriction; free radical oxygen; gene expression; gene targeting; genetically modified animals; hypothalamus; laboratory mouse; lipids; membrane transport proteins; microarray technology; mitochondrial membrane; neuritis; nutrition related tag; oxidative stress; peroxidation; protein structure function; striated muscles

DESCRIPTION (provided by applicant): Caloric restriction (CR) extends mean and maximum life span via mechanisms that are not delineated. One hypothesis is that CR acts by reducing oxidative stress [generation of and/or damage from reactive oxygen species (ROS)]. Supporting this are data showing that CR reduces oxidative stress/damage; but no causal relationship between oxidative stress and life span has been proven, due in part to lack of an appropriate animal model. We have transgenic mice that over express mitochondrial uncoupling proteins (UCP)-2 and 3, decreasing protonmotive force and presumably resulting in mitochondria that generate less ROS. In 6-month-old transgenics, brain areas with high UCP2 expression have less lipid peroxidation and neural inflammation than do the wild type; and after a neural trauma, transgenics show less apoptosis. In contrast, UCP3 knockouts have muscle mitochondria that generate more ROS and exhibit more oxidative damage. These data suggest strongly that elevated UCP2/3 expression in ad libitum-fed mice mimics CR with respect to oxidative stress. We will test this by measuring ROS generation, lipid & protein damage, and apoptosis in skeletal muscle (UCP3 expression), hypothalamus (UCP2 expression), and liver (no significant UCP2 or 3 expression) at 4 ages over the life span. We will also determine if transgenics live longer as do CR mice. While we hypothesize that this is the case, a finding to the contrary (no extension of median/maximum life span in transgenics despite less oxidative damage) would argue against causal links between the two phenomena. We will evaluate UCP2/3 transgenics, UCP2 & UCP3 knockouts, wild type fed ad lib, and CR wild type mice for median/maximum life span, mitochondrial ROS, gene expression patterns (via microarrays), oxidative damage, apoptosis/cell death, and neural inflammation. If increased expression of UCP2/3 mimics caloric restriction, changes should be qualitatively similar to those in CR wild type mice, with changes in the opposite direction for the knockouts. Finally, we hypothesize that the life- extending effects of increased UCP2/3 expression will occur without decreases in total energy expenditure or circulating glucose (i.e., that neither is critical to life extension). Our data will determine if greater expression of UCP2/3 mimics effects of CR and will increase our understanding of mechanisms that have potential to increase median and maximum life span.

描述（由申请人提供）：热量限制（CR）延长平均值， 通过未描述的机制实现最大寿命。 一个假设是 CR通过减少氧化应激[产生和/或损伤 活性氧（ROS）。 支持这一点的数据显示，CR 减少氧化应激/损伤;但氧化应激/损伤之间没有因果关系 压力和寿命已被证明，部分原因是缺乏适当的 动物模型 我们有过表达线粒体的转基因小鼠， 解偶联蛋白（UCP）-2和3，降低质子动力， 推测导致线粒体产生较少的ROS。 在6个月大时 在转基因动物中，UCP 2高表达的大脑区域的脂质含量较少， 过氧化和神经炎症比野生型;和神经后 创伤，转基因显示较少的凋亡。 相比之下，UCP 3敲除具有 肌肉线粒体产生更多的ROS，并表现出更多的氧化损伤。 这些数据有力地表明，在自由进食的小鼠中，UCP 2/3表达升高， 小鼠在氧化应激方面模仿CR。 我们将测试这一点， 测量骨骼肌中ROS的产生、脂质和蛋白质损伤以及细胞凋亡 肌肉（UCP 3表达）、下丘脑（UCP 2表达）和肝脏（无 UCP 2或3表达显著）。 我们还将 确定转基因小鼠是否像CR小鼠一样活得更长。 我们假设 这是一个相反的发现（没有中位数/最大值的扩展）。 寿命在转基因尽管较少氧化损伤）将反对 这两种现象之间的因果关系。 我们将评估UCP 2/3转基因， UCP 2和UCP 3敲除、野生型自由进食和CR野生型小鼠， 中位/最长寿命，线粒体ROS，基因表达模式（通过 微阵列）、氧化损伤、凋亡/细胞死亡和神经炎症。 如果UCP 2/3表达增加与热量限制相似， 与CR野生型小鼠中的那些定性相似， 与击倒方向相反 最后，我们假设- UCP 2/3表达增加的延长效应将在不降低UCP 2/3表达的情况下发生。 在总能量消耗或循环葡萄糖（即，两者都不是 寿命延长的关键）。 我们的数据将决定是否更多的表达 UCP 2/3模拟CR的作用，并将增加我们对机制的理解 有可能延长中位寿命和最长寿命。