Anti-aging effects of PGC-1 alpha expression

PGC-1 α表达的抗衰老作用

基本信息

批准号：
7273623
负责人：
WALTER Frederick WARD
金额：
$ 5.81万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-15 至 2008-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7273623
关键词：
Acetylation Achievement Activities of Daily Living Address Adipose tissue Affect Age Aging Aging-Related Process Amino Acids Animals Binding Biogenesis Biological Biological Models Brown Fat Caloric Restriction Complex Cytochrome c1 DNA DNA Binding Data Diquat Energy Metabolism Enzymes Exhibits Family Family member Generations Genes Genetic Transcription Gold Grant Gray unit of radiation dose Hepatic Homeostasis Human Intervention Isoprostanes Kidney Ligands Link Lipids Liver Longevity Maintenance Measures Mediating Messenger RNA Metabolic Metabolism Mitochondria Mitochondrial DNA Modification Molecular Monitor Mus Muscle Fibers Nematoda Nuclear Nuclear Hormone Receptors Organism Oxidative Stress PPAR gamma Paraquat Peroxisome Proliferator-Activated Receptors Peroxisome Proliferators Personal Communication Physiological Play Process Production Protein Analysis Proteins Quality of life Range Rate Reactive Oxygen Species Regulation Relative (related person)Rodent Role Signal Pathway Skeletal Muscle Standards of Weights and Measures Structure Superoxides Testing Thermogenesis Thinking Thyroid Hormone Receptor Time Tissue Differentiation Tissues Transcription Coactivator Transcriptional Regulation Transgenes Transgenic Animals Transgenic Organisms Western Blotting Wild Type Mouse Yeasts age effect age related animal tissue anti aging base carbonyl group cytochrome c oxidase gene therapy glucose metabolism insight interest lipid biosynthesis lipid metabolism member mouse model novel programs protective effect response transcription factor uncoupling protein 1

项目摘要

DESCRIPTION (provided by applicant): The functional capacity of the mitochondrion is actively regulated to meet the energy requirements of mammalian organisms. The regulation of mitochondrial biogenesis involves multiple transcriptional and signaling pathways that modulate the expression of nuclear and mitochondrial genes that are involved in mitochondrial structure, metabolism and proliferation. The transcriptional co activator, peroxisome proliferator-activated receptor-gamma (PPARy) coactivator-1alpha (PGC-1a) is thought to integrate the molecular regulatory circuitry involved in the transcriptional control of cellular energy metabolism, including mitochondrial function and biogenesis. We have developed a unique transgenic mouse model that over-expresses PGC-1a. Preliminary data suggests this animal exhibits metabolic alterations that are analogous to caloric restriction, which has been shown to alter the aging process and extend lifespan. Thus our hypothesis is over-expression of PGC-1a will have an anti-aging action in mice. Mitochondria have been proposed to be an important link between the age-related accumulation of oxidative damage caused by reactive oxygen species and the alterations of physiological function associated with aging. One of the major actions of PGC-1a is the induction of mitochondrial biogenesis. The first specific aim will therefore be to determine if mitochondrial biogenesis has indeed been induced in skeletal muscle, adipose tissue and liver by measuring mitochondrial enzyme and protein levels utilizing real time-PCR for mRNA and Western blot analysis for protein. Specific aim 2 will address the question of whether over-expression of PGC-1a has a protective effect against oxidative damage due to mitochondrial production of reactive oxygen species, as caloric restriction does. Oxidative damage of hepatic lipid, DNA and protein will be determined by measuring isoprostane, oxoSdG and carbonyl group formation, respectively. Specific aim 3 will be a longevity study in which we will determine whether the median life span of the transgenic animals is altered. The long-term objectives of this application are to determine if over-expression of PGC-1a extends the life span of the transgenic animal and, if so, to then determine a mechanism of action for that effect. Insights gained into the mechanisms of life-span extension will increase the likelihood of identifying physiologic or pharmacologic interventions that may enable us to increase human lifespan and/or quality of life. In this context, a better understanding of the molecular processes involved in age-related deteriorative processes, such as oxidative modifications, will uncover approaches for such interventions.

描述（由申请人提供）：线粒体的功能能力受到积极调节，以满足哺乳动物生物体的能量需求。线粒体生物发生的调节涉及多种转录和信号传导途径，这些途径调节参与线粒体结构、代谢和增殖的核和线粒体基因的表达。转录辅激活剂过氧化物酶体增殖物激活受体-γ (PPARy) 辅激活剂-1α (PGC-1a) 被认为整合了参与细胞能量代谢转录控制的分子调节电路，包括线粒体功能和生物发生。我们开发了一种独特的转基因小鼠模型，该模型过度表达 PGC-1a。初步数据表明，这种动物表现出类似于热量限制的代谢变化，这已被证明可以改变衰老过程并延长寿命。因此，我们的假设是 PGC-1a 的过度表达将在小鼠中具有抗衰老作用。线粒体被认为是活性氧引起的与年龄相关的氧化损伤积累和与衰老相关的生理功能改变之间的重要联系。 PGC-1a 的主要作用之一是诱导线粒体生物发生。因此，第一个具体目标是通过使用实时 PCR 检测 mRNA 和蛋白质印迹分析测量线粒体酶和蛋白质水平，确定骨骼肌、脂肪组织和肝脏中是否确实诱导了线粒体生物合成。具体目标 2 将解决 PGC-1a 的过度表达是否对线粒体产生活性氧造成的氧化损伤具有保护作用，就像热量限制一样。肝脂质、DNA 和蛋白质的氧化损伤将分别通过测量异前列烷、oxoSdG 和羰基形成来确定。具体目标 3 将是一项长寿研究，我们将确定转基因动物的中位寿命是否发生改变。本申请的长期目标是确定 PGC-1a 的过度表达是否会延长转基因动物的寿命，如果是的话，则确定该效果的作用机制。对寿命延长机制的深入了解将增加识别生理或药物干预措施的可能性，这些干预措施可能使我们能够延长人类寿命和/或生活质量。在这种情况下，更好地了解与年龄相关的退化过程（例如氧化修饰）所涉及的分子过程，将揭示此类干预措施的方法。