Proteasome Function During Aging in Extraordinarily Long-Lived Naked Mole-Rats

超长寿命裸鼹鼠衰老过程中的蛋白酶体功能

基本信息

批准号：
8726270
负责人：
ROCHELLE BUFFENSTEIN
金额：
$ 18.69万
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：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2015-07-03
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8726270
关键词：
Activities of Daily Living Address Age Aging Alzheimer&apos s Disease Animal Model Animals Attention Attenuated Autophagocytosis Biological Preservation Brain Catalytic Domain Cleaved cell Complex Core Assembly Cytosol Data Deterioration Development Diquat Disease Dose Elderly Employee Strikes Environment Excision Free Radicals Functional disorder Future Gel Chromatography Genetic Crossing Over Goals Health Health Benefit Heat shock proteins Homeostasis Hour Housing Immune Immunoprecipitation In Vitro Individual Intervention Laboratory mice Lead Life Link Lipids Liver Longevity Maintenance Measures Mediating Mitotic Mole Rats Molecular Molecular Chaperones Mus Muscle NF-kappa B Nature Onset of illness Oxidative Stress Pathology Pathway interactions Pharmaceutical Preparations Play Population Process Property Proteins Quality Control Quality of life Reaction Reliance Research Resistance Rodent Role Specificity Spleen Stress Structure Subcellular Fractions Testing Time Tissues Ultracentrifugation age related aged analytical ultracentrifugation base cohort environmental stressor functional decline healthy aging heat-shock factor 1 in vivo inhibitor/antagonist insight multicatalytic endopeptidase complex novel nuclear factor-erythroid 2 protein aggregate protein misfolding public health relevance research study response senescence small molecule species difference stressor trend uptake

项目摘要

DESCRIPTION (provided by applicant): The accrual of damaged or misfolded proteins commonly occurs during aging. Indeed, protein dysfunction is a key feature of many age-associated diseases. As such maintenance of protein quality control may be central to sustained healthspan and extended longevity. The longest-lived rodents, naked mole-rats [NMRs], maintain proteostasis and robust health for most of their 32-year lifespan. NMRs also show marked resistance to environmental stressors, and efficiently preserve protein quality. Both autophagy and proteasome-mediated degradation [PMD] play critical roles in intracellular protein quality control. We focus here on PMD for it is a key player in the removal of oxidatively damaged proteins and reportedly declines with age. We hypothesize that NMRs maintain highly efficient PMD in mitotic (e.g., liver), terminally-differentiated (brain, muscle) and immune-responsive (spleen) tissues during aging and that this is due to intrinsic properties of the proteasome [PRS] and/or a cytoprotective intracellular milieu. We address this in the following specific aims: Aim 1. To evaluate PRS structure and function, and in particular the role of the immunoproteasome [IMPR], in specific differences in PRS functional capacity, both during aging and in response to in vivo oxidative stressors. We hypothesize that the PRSs of NMRs are well-suited to effectively respond to oxidative stress and predict that this is due, in part, to the greter abundance of IMPRs. We will measure both age-related and oxidative stress-induced changes in PRS structure, functional capacity, and intracellular distribution in the various tissues. Our preliminary data reveal 2-5-fold higher rates of ChTL and TL activities, and higher diversity of PRS assemblies in NMR than in mouse livers. We expect to find similar trends in other tissues, especially in response to drug-induced oxidative stress, and predict a new role of IMPRs in preserving the efficacy of PMD. Aim 2. To determine whether interspecies differences in PRS capacity are due to intrinsic properties of the PRS and/or the intracellular environment. Here we introduce a novel concept of cytosolic-based protection of the PRSs in NMR. We hypothesize that heat shock proteins [HSPs] play a key role in PMD, especially under oxidative stress. Our preliminary data suggest that HSPs confer resistance to PRS specific inhibitors in NMRs. We assess the molecular composition and function of the "resistasome", the protein assembly that protects PRSs from inhibition/stress, in several NMR tissues during aging and drug-induced oxidative stress. We expect that NMR PRSs are universally well-protected by the resistasome. We envision future development of resistasome-inspired drugs or interventions aimed at boosting PMD efficacy. These studies use an unusually long-lived rodent to gain novel insights into mechanisms enabling the stability and maintenance of elevated PRS function. Understanding these will help foil the many age-related diseases linked to inadequate PRS-mediated degradation and the accrual of damaged proteins in the elderly.

描述（由申请人提供）：受损或错误折叠蛋白质的累积通常发生在衰老过程中。事实上，蛋白质功能障碍是许多与年龄相关的疾病的一个关键特征。因此，维持蛋白质质量控制可能是维持健康寿命和延长寿命的核心。寿命最长的啮齿动物，裸鼹鼠 [NMR]，在其 32 年寿命的大部分时间里都保持着蛋白质稳态和强健的健康状况。 NMR 还显示出对环境压力的显着抵抗力，并有效保持蛋白质质量。自噬和蛋白酶体介导的降解 [PMD] 在细胞内蛋白质质量控制中发挥着关键作用。我们在这里重点关注 PMD，因为它是去除氧化损伤蛋白质的关键因素，据报道，它会随着年龄的增长而下降。我们假设 NMR 在衰老过程中在有丝分裂（例如肝脏）、终末分化（大脑、肌肉）和免疫反应（脾脏）组织中维持高效的 PMD，这是由于蛋白酶体 [PRS] 和/或细胞保护性细胞内环境。我们通过以下具体目标来解决这个问题：目标 1. 评估 PRS 的结构和功能，特别是免疫蛋白酶体 [IMPR] 的作用，在衰老过程中和响应体内氧化应激源时 PRS 功能能力的具体差异中。我们假设 NMR 的 PRS 非常适合有效应对氧化应激，并预测这部分是由于 IMPR 的丰度更高。我们将测量与年龄相关和氧化应激引起的 PRS 结构、功能能力和各种组织中细胞内分布的变化。我们的初步数据显示，与小鼠肝脏相比，NMR 中的 ChTL 和 TL 活性高出 2-5 倍，PRS 组装的多样性也更高。我们期望在其他组织中发现类似的趋势，特别是在响应药物诱导的氧化应激方面，并预测 IMPR 在保持 PMD 功效方面的新作用。目标 2. 确定 PRS 能力的种间差异是否是由于 PRS 和/或细胞内环境的内在特性造成的。在这里，我们介绍了 NMR 中基于胞质的 PRS 保护的新概念。我们假设热休克蛋白 [HSP] 在 PMD 中发挥关键作用，特别是在氧化应激下。我们的初步数据表明，HSP 赋予 NMR 中 PRS 特异性抑制剂抗性。我们评估了衰老和药物诱导的氧化应激过程中几种 NMR 组织中“抗性体”（保护 PRS 免受抑制/应激的蛋白质组装体）的分子组成和功能。我们预计 NMR PRS 普遍受到抗性体的良好保护。我们设想未来开发抗药性药物或干预措施，旨在提高 PMD 疗效。这些研究使用异常长寿的啮齿动物来获得对 PRS 功能稳定和维持的机制的新见解。了解这些将有助于阻止许多与年龄相关的疾病，这些疾病与老年人中 PRS 介导的降解不足和受损蛋白质的累积有关。