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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：
9751135
负责人：
GR Scott Budinger
金额：
$ 199.26万
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/9751135
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 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 pathogenic bacteria pathogenic virus 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）：老化的肺导致老年人失去弹性和脆弱性，损害健康寿命-减少免于残疾，疼痛和独立的持续时间。改善健康寿命和减少老龄化的社会和经济负担的干预策略需要针对可延展系统的新方法，这些方法可以提高弹性并减少老化肺对病原体和其他环境因子的脆弱性。蛋白质稳态是指细胞通过调控网络系统控制组成蛋白质组的单个蛋白质的浓度、构象、结合相互作用和位置的动态过程。细胞中蛋白质稳态网络的功能障碍是衰老表型中常见的最终途径，并且在模型生物体的衰老过程中下降;然而，缺乏生物学相关技术来测量哺乳动物肺中的这些变化和/或检查其对器官生理学的影响。PPG的研究人员开发了新的基于发光和质谱的技术，以测量肺中的蛋白质稳态，他们使用该技术来检查肺中蛋白质稳态网络在衰老和甲型流感病毒感染期间的功能，甲型流感病毒是临床上重要的肺损伤模型。季节性和大流行性甲型流感感染在老年人中造成不成比例的发病率和死亡率。严重感染导致定义急性呼吸窘迫综合征（ARDS）的双侧肺浸润和低氧血症，这是每年20，000 - 50，000例甲型流感感染患者死亡的主要原因。项目负责人使用该系统在三个高度集成的项目中探测衰老过程中蛋白质稳态网络的脆弱性，丹项目1将检验以下假设：在寿命期内，用骨髓来源的肺泡巨噬细胞替换组织驻留的肺泡巨噬细胞池会损害蛋白质稳态，从而增加老年小鼠对甲型流感感染的易感性。项目2将验证线粒体呼吸链能力降低促进上皮蛋白质稳态以减轻衰老过程中流感病毒引起的肺损伤的假设。项目3将检验以下假设：老年甲型流感感染小鼠对骨骼肌功能障碍的易感性增强是由于来自肺部的信号传导（破坏蛋白质稳态）和来自肺部的信号传导（诱导保护性热休克反应）之间的平衡改变所致。项目负责人将联合收割机遗传和药理学干预结合起来，预测在感染甲型流感病毒前后增强或损害衰老小鼠的蛋白质抑制功能，并对蛋白质抑制网络（核心B）和肺和骨骼肌生理学（核心C）的功能进行复杂评估，以建立哺乳动物系统中衰老、蛋白质抑制与肺和骨骼肌功能障碍之间的因果关系，为人类衰老提供了重要的机制和治疗见解。