Caveolin 1: a novel modulator of the PP2A/ATM/p53 pathway

Caveolin 1：PP2A/ATM/p53 通路的新型调节剂

基本信息

批准号：
7903303
负责人：
FERRUCCIO GALBIATI
金额：
$ 30.25万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7903303
关键词：
Affect Age Aging Aging-Related Process American Ataxia-Telangiectasia-Mutated protein kinase Cause of Death Caveolae Cell Aging Cells Chronic Obstructive Airway Disease Cigarette smoke-induced emphysema DNA Damage Data Diploidy Disease Dissociation Embryo Environmental Hazards Event Excision Failure Fibroblasts Genotoxic Stress Human Interphase Cell Investigation Knockout Mice Laboratories Link Lung Maintenance Mediating Membrane Membrane Microdomains Molecular Mus Organism Oxidants Oxidative Stress Pathogenesis Pathway interactions Phenotype Phosphoric Monoester Hydrolases Play Prevention Protein p53 Protein phosphatase Proteins Pulmonary Emphysema Regulation Role Signal Transduction Source Stress Structural Protein TP53 gene Testing Tumor Suppressor Proteins Up-Regulation age related ataxia telangiectasia mutated protein caveolin 1 cigarette smoke-induced cigarette smoking complement C2a human disease in vivo inhibitor/antagonist insight new therapeutic target novel phosphatase inhibitor premature public health relevance repaired senescence therapeutic target

项目摘要

DESCRIPTION (provided by applicant): One of the manifestations of aging is the accumulation of damage at both cellular and organism levels. Genotoxic stress plays an important role in aging and age-related diseases such as emphysema, which is caused by a failure of lung maintenance and repair after sustained oxidative stress. Cigarette smoke represents a source of oxidants and is considered an environmental hazard that causes pulmonary emphysema. Premature senescence is believed to contribute to genotoxic stress-induced emphysema. The tumor suppressor protein p53 is a key regulator of premature senescence and is activated by the ataxia-telangiectasia mutated (ATM) protein kinase when the ATM inhibitor protein phosphatase 2A (PP2A) dissociates from ATM after genotoxic stress. The mechanism underlying PP2A-C removal from ATM upon genotoxic stress remains totally unexplored. In addition, the role that the ATM/p53 pathway plays in cigarette smoke-induced cellular senescence and the pathogenesis of emphysema remains largely unknown. Here, we plan to test the hypothesis that the lipid raft protein caveolin-1 mediates stress-induced premature senescence by promoting ATM-dependent activation of p53 through sequestration of the ATM inhibitor PP2A-C into caveolae. In addition, it is hypothesized that caveolin-1 plays a central role in oxidant-promoted emphysema in vivo through induction of cellular senescence. This hypothesis will be tested by pursuing three specific aims: Specific Aim 1: Investigate the role of caveolin-1 in PP2A-mediated regulation of ATM function after genotoxic stress. Specific Aim 2: Determine the functional consequences of loss of caveolin-1 expression on ATM-mediated p53 activation and premature senescence. Specific Aim 3: Define the role of caveolin-1 in genotoxic stress-induced pulmonary emphysema in vivo. These studies will provide novel insights into the signaling machinery that links genotoxic stress to cellular senescence and propose caveolin-1 as a novel therapeutic target for the treatment of age-related diseases such as emphysema. PUBLIC HEALTH RELEVANCE: Oxidative stress, including cigarette smoke, promotes premature cellular senescence, which is believed to have an important role in the more complicated aging process, and contributes to age-related diseases like emphysema. The molecular mechanisms underlying cigarette smoke-induced emphysema are not fully understood. Our studies will test the hypothesis that the protein caveolin-1 is a novel regulator of stress-induced cellular senescence and emphysema, and propose caveolin-1 as an alternative therapeutic target for the treatment of age-related diseases such as emphysema.

描述（由申请人提供）：衰老的表现之一是在细胞和生物水平上均积累损害。遗传毒性应激在衰老和与年龄有关的疾病（例如肺气肿）中起重要作用，这是由于持续的氧化应激后肺部维持和修复失败引起的。香烟烟代表氧化剂的来源，被认为是导致肺气肿的环境危害。据信过早衰老有助于遗传毒性应激诱导的肺气肿。肿瘤抑制蛋白p53是过早衰老的关键调节剂，当ATM抑制剂蛋白磷酸酶2A（PP2A）在遗传毒性应激后与ATM分离时，被共济型 - 催化性突变（ATM）蛋白激酶激活。在遗传毒性应力下，从ATM中去除PP2A-C的基础机制仍然完全没有探索。另外，ATM/p53途径在香烟烟雾诱导的细胞衰老和肺气肿的发病机理中发挥作用。在这里，我们计划检验以下假设：脂质筏蛋白可窝蛋白-1通过通过固并ATM抑制剂PP2A-C中的ATM依赖性激活p53促进压力诱导的过早衰老。此外，假设小窝蛋白1通过诱导细胞衰老而在体内氧化剂促进性肺气肿中起着核心作用。该假设将通过追求三个特定目的来检验：特定目的1：研究小窝蛋白1在遗传毒性应激后对ATM功能调节的作用。具体目标2：确定在ATM介导的p53激活和早衰老中，小窝蛋白-1表达丧失的功能后果。具体目标3：定义小窝蛋白-1在体内遗传毒性应激诱导的肺肺气肿中的作用。这些研究将提供有关将遗传毒性应激与细胞衰老联系起来的信号机械的新见解，并提出小窝蛋白-1作为治疗与年龄相关疾病（如肺气肿）的新型治疗靶标。公共卫生相关性：包括香烟烟雾在内的氧化应激会促进过早的细胞衰老，据信这在更复杂的衰老过程中起着重要作用，并有助于与年龄相关的疾病，例如肺气肿。香烟烟雾引起的肺气肿的分子机制尚不完全了解。我们的研究将检验以下假设：蛋白质可窝蛋白-1是应激诱导的细胞衰老和肺气肿的新型调节剂，并提出小窝蛋白-1作为治疗年龄相关疾病（如肺气肿）的替代治疗靶标。