Disordered Proteostasis as a Driver of Disease in the Aging Lung

蛋白质稳态紊乱是衰老肺疾病的驱动因素

基本信息

批准号：
9779491
负责人：
GR Scott Budinger
金额：
$ 4.89万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9779491
关键词：
Acute Address Adult Respiratory Distress Syndrome Age Aging Air Alveolar Macrophages Animal Model Animals Attenuated Bilateral Binding Biological Blood Bone Marrow Caenorhabditis elegans Carbon Dioxide Cause of Death Cells Cessation of life Charge Chronic lung disease Climate Clinical Communities Data Development Disease Economic Burden Environmental Risk Factor Epithelial Equilibrium Freedom Functional disorder Genetic Genetic Risk Goals Heat-Shock Response Human Human Biology Hypoxemia Image Impairment Individual Infection Influenza A virus Intervention Laboratories Link Location Longevity Lung Lung diseases Maintenance Mammals Maps Mass Spectrum Analysis Measures Metabolic Mitochondria Modeling Molecular Molecular Conformation Morbidity - disease rate Mus Organ Oxidative Phosphorylation Pain Pathway interactions Patients Pharmacology Phenotype Physiological Physiology Play Population Predisposition Process Program Research Project Grants Proteins Proteome Proteomics Reporting Research Research Personnel Respiratory Chain Respiratory Failure Respiratory physiology Role Scientist Signal Transduction Skeletal Muscle Stress System Techniques Testing Therapeutic Time Tissues United States Viral Woman Work age related aged aging population attributable mortality base cigarette smoke clinical development clinically relevant disability environmental agent frailty healthspan improved insight luminescence lung basal segment lung development lung injury man mortality muscle physiology normal aging novel novel strategies oxygen transport pandemic influenza pathogen pollutant programs proteostasis public health relevance resilience response seasonal influenza social tool

项目摘要

DESCRIPTION (provided by applicant): The aging lung contributes to the loss of resiliency and frailty in the aging population that impairs the healthspan--reducing the duration of freedom from disability, pain and independence. Interventional strategies to improve healthspan and reduce the social and economic burdens of aging require novel approaches targeting malleable systems that improve resiliency and reduce frailty of the aging lung in response to pathogens and other environmental agents. Proteostasis refers to the dynamic process by which cells control the concentration, conformation, binding interactions, and location of individual proteins making up the proteome through a system of regulated networks. Dysfunction in the proteostasis networks in the cell is a common final pathway in aging phenotypes and declines during aging in model organisms; however, biologically relevant techniques to measure these changes in the mammalian lung and/or examine their consequences for organ physiology have been lacking. The investigators in this PPG have developed novel luminescence- and mass-spectroscopy-based techniques, to measure proteostasis in the lung, which they use to examine the function of the proteostasis networks in the lung during aging and during infection with the influenza A virus, a clinically important model of lung injury. Seasonal and pandemic influenza A infection cause disproportionate morbidity and mortality in older individuals. Severe infection results in the bilateral pulmonary infiltrates and hypoxemia that define the Acute Respiratory Distress Syndrome (ARDS), which is the primary cause of the 20,000-50,000 deaths in patients with influenza A infection each year. The Project Leaders use this system to probe the frailty of the proteostasis networks during aging in three highly integrated Projects and Cores. Project 1 will test the hypothesis that replacement of the tissue-resident alveolar macrophage pool with bone marrow derived alveolar macrophages over the lifespan impairs proteostasis to increase the susceptibility to influenza A infection in aged mice. Project 2 will tst the hypothesis that reducing mitochondrial respiratory chain capacity promotes epithelial proteostasis to attenuate influenza A virus-induced lung injury during aging. Project 3 will test the hypothesis that the enhanced susceptibility of aged, influenza A infected mice to skeletal muscle dysfunction results from an altered balance between signaling from the lung that disrupts proteostasis and signaling from the lung that induces a protective heat shock response. The Project Leaders combine genetic and pharmacologic interventions predicted to enhance or impair proteostatic function in aging mice before and after infection with the influenza A virus with sophisticated assessments of the function of the proteostasis networks (Core B) and lung and skeletal muscle physiology (Core C) to establish causal links between aging, proteostasis, and lung and skeletal muscle dysfunction in a mammalian system, providing important mechanistic and therapeutic insights into human aging.

描述（由申请人提供）：衰老的肺部造成了损害HealthSpan的衰老人群的弹性和脆弱性的损失，从而减少了免受残疾，疼痛和独立性的自由。介入的改善健康范围并减轻衰老的社会和经济负担的介入策略需要针对可锻造系统的新方法，以提高弹性并减少肺部肺活量的脆弱性，以响应病原体和其他环境药物。 Proteostasis是指细胞控制浓度，构象，结合相互作用以及通过调节网络系统组成蛋白质组的单个蛋白质的位置的动态过程。细胞中蛋白质量的网络的功能障碍是模型生物衰老期间衰老表型和下降的常见最终途径。但是，缺乏与哺乳动物肺中这些变化和/或检查其对器官生理的后果的生物学相关技术。该PPG中的研究人员开发了基于新型的发光和质量 - 光谱的技术，以测量肺中的蛋白抑制作用，他们用来检查肺部蛋白抑制性网络在衰老期间肺部蛋白抑制网络的功能，并在感染流感病毒期间，这是一种临床上重要的肺损伤模型。季节性和大流行性流感感染会导致老年人的发病率和死亡率不成比例。严重的感染导致双侧肺浸润和低氧血症定义急性呼吸遇险综合征（ARDS），这是每年流感A感染患者20,000-50,000例死亡的主要原因。项目负责人使用该系统在三个高度集成的项目中衰老期间探讨蛋白质量网络的脆弱性内核。项目1将检验以下假设：在整个生命周期中，用骨髓衍生的肺泡巨噬细胞替代组织居住的肺泡巨噬细胞池会损害蛋白质的肺泡，从而增加对老年小鼠感染的流感感染的易感性。项目2将提出一个假设，即降低线粒体呼吸链能力可促进上皮蛋白质抗体，从而减轻衰老期间病毒诱导的肺损伤的流感。项目3将检验以下假设：衰老，流感A感染的小鼠对骨骼肌功能障碍的敏感性增强，这是由于肺部信号传导之间的平衡发生了变化，从而破坏了蛋白质的肺部和肺部信号传导，从而诱导了保护性热冲击反应。该项目领导者结合了预计将在感染前后与流感病毒感染前后增强或损害遗传学和药理学干预措施，以及对蛋白质抑制性网络（核心B）和肺部和骨骼肌肉生理学（Core c）的功能的复杂评估，以建立蛋白质互动（Core c）之间的蛋白质效果（核心B）和蛋白质互动，并在脂肪中互动，并在脂肪中互动，以及蛋白质群体，以及蛋白质群体，以及蛋白质的蛋白质群体，并构成了Skerfs unguns ungunt ins the neepff。哺乳动物系统，为人类衰老提供重要的机械和治疗见解。