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

• 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
• 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' 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

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（由申请方提供）：老化过程中通常会出现受损或错误折叠的蛋白质。事实上，蛋白质功能障碍是许多年龄相关疾病的关键特征。因此，保持蛋白质质量控制可能是持续健康和延长寿命的核心。寿命最长的啮齿类动物，裸鼹鼠[NMR]，在其32年寿命的大部分时间内保持蛋白质稳定和健康。NMR还显示出对环境压力的显著抗性，并有效地保持蛋白质质量。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起关键作用。我们在这里关注PMD，因为它是去除氧化损伤蛋白质的关键因素，据报道随着年龄的增长而下降。我们假设NMR在有丝分裂中维持高效PMD（例如，肝脏）、终末分化（脑、肌肉）和免疫应答（脾）组织，这是由于蛋白酶体[PRS]的内在特性和/或细胞保护性细胞内环境。我们在以下具体目标中处理这一问题：目标1。评价PRS结构和功能，特别是免疫蛋白酶体[IMPR]在老化期间和对体内氧化应激的反应中PRS功能能力的特定差异中的作用。我们假设NMR的PRS非常适合有效地应对氧化应激，并预测这部分是由于IMPR的丰度更高。我们将测量年龄相关的和氧化应激诱导的PRS结构，功能能力和细胞内分布在各种组织中的变化。我们的初步数据显示，2-5倍高速率的ChTL和TL的活动，和更高的多样性的PRS组件在NMR比小鼠肝脏。我们希望在其他组织中发现类似的趋势，特别是在对药物诱导的氧化应激的反应中，并预测IMPR在保持PMD疗效方面的新作用。目标2.确定PRS能力的种间差异是否是由于PRS和/或细胞内环境的固有特性。在这里，我们介绍了一个新的概念，基于细胞溶质的保护的PRS在NMR。我们推测热休克蛋白（HSP）在PMD中起关键作用，特别是在氧化应激下。我们的初步数据表明，热休克蛋白赋予耐药的PRS特异性抑制剂的NMR。我们评估的分子组成和功能的“resistasome”，蛋白质组装，保护PRSs从抑制/压力，在几个NMR组织在老化和药物诱导的氧化应激。我们预期NMR PRS普遍受到抵抗体的良好保护。我们设想未来开发抵抗酶体激发的药物或干预措施，旨在提高PMD的疗效。这些研究使用了一种寿命异常长的啮齿动物，以获得对能够稳定和维持升高的PRS功能的机制的新见解。了解这些将有助于阻止许多与老年人中不充分的PRS介导的降解和受损蛋白质累积相关的年龄相关疾病。