权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mitochondrial biogenesis, genetics and cell loss in mammalian aging

哺乳动物衰老过程中的线粒体生物发生、遗传学和细胞损失

基本信息

批准号：
9767003
负责人：
Jonathan Wanagat
金额：
$ 16.02万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9767003
关键词：
Affect Age Age-Years Aging American Animals Apoptosis Atrophic Bezafibrate Biogenesis Caloric Restriction Cell Death Cells Chronic Clinical Clinical Trials Creatine Data Deletion Mutation Electron Transport Event Fiber Frequencies Funding Gene Expression Genes Genetic Genome Human Independent Scientist Award Individual Intervention Length Link Longevity Measures Metformin Mitochondria Mitochondrial DNA Muscle Muscle Cells Muscle Fibers Muscle function Muscular Atrophy Mutation Necrosis Pathway interactions Pharmaceutical Preparations Phenotype Pioglitazone Proteins Public Health Rattus Replication Error Research Role Sirolimus Skeletal Muscle Specific qualifier value Structure Testing Time Tissues Up-Regulation aged analog base dosage frailty genetic approach guanidinopropionic acid in vivo loss of function mitochondrial genome muscle aging mutant pleiotropism preservation quadriceps muscle research and development transcription factor translation factor treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT Mitochondrial biogenesis is a target of many aging interventions. While the induction of mitochondrial biogenesis is generally thought to be beneficial, our data indicate that activating mitochondrial biogenesis at old age drives the intracellular accumulation of mitochondrial DNA (mtDNA) deletion mutations and results in an 18% loss of muscle fibers and a 1,200% increase in electron transport chain (ETC) deficient muscle fiber segments. These effects were antagonistically pleiotropic; they were not observed in treated young rats. Based on our data, up-regulation of mitochondrial biogenesis in aged humans may cause significant skeletal muscle damage. These studies will clarify the role of mitochondrial biogenesis in mtDNA deletion mutation accumulation and evaluate the old-age specific effects of compounds that stimulate mitochondrial biogenesis in skeletal muscle. This project will: define the antagonistic pleiotropy of mitochondrial biogenesis in muscle fiber loss; test the hypothesis that mtDNA deletion genome accumulation drives fiber loss; specify the order of events and time required between mitochondrial biogenesis, mtDNA deletion mutation accumulation and cell death; refine proposed mechanisms for deletion accumulation; determine if geroprotectors, which target mitochondrial biogenesis, antagonistically induce mtDNA deletion mutation accumulation. By understanding the mechanisms of inducing mitochondrial biogenesis at old ages, we will specify targets and treatment strategies that mitigate the antagonistic effects. This K02 award, if funded, will protect the candidate's research time from overextended clinical and administrative duties to allow further research development.

项目总结/摘要线粒体生物发生是许多衰老干预的目标。虽然诱导线粒体生物发生通常被认为是有益的，我们的数据表明，激活线粒体生物发生，老年驱动线粒体DNA（mtDNA）缺失突变的细胞内积累，肌肉纤维减少18%，电子传递链（ETC）缺陷的肌肉纤维增加1,200% 片段这些作用具有拮抗多效性;在给药的幼龄大鼠中未观察到。基于根据我们的数据，老年人线粒体生物合成的上调可能会导致骨骼肌显着增加损害这些研究将阐明线粒体生物发生在mtDNA缺失突变中的作用积累，并评估刺激线粒体生物发生的化合物的老年特异性作用在骨骼肌中。本项目将：明确肌肉线粒体生物合成的拮抗多效性纤维丢失;检验mtDNA缺失基因组积累驱动纤维丢失的假设;指定线粒体生物发生、mtDNA缺失突变积累和细胞增殖之间的事件和时间死亡;完善删除累积的拟议机制;确定老年保护者，线粒体生物合成，拮抗性诱导mtDNA缺失突变积累。通过了解诱导老年线粒体生物合成的机制，我们将指定目标和治疗缓解对抗效应的策略。这个K 02奖，如果资助，将保护候选人的研究从过度临床和行政职责中抽出时间，以便进行进一步的研究开发。