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）：衰老的表现之一是细胞和有机体水平损伤的积累。基因毒性应激在衰老和与年龄相关的疾病（例如肺气肿）中发挥着重要作用，肺气肿是由持续氧化应激后肺部维护和修复失败引起的。香烟烟雾是氧化剂的来源，被认为是导致肺气肿的环境危害。据信过早衰老会导致基因毒性应激诱发的肺气肿。肿瘤抑制蛋白 p53 是过早衰老的关键调节因子，当 ATM 抑制剂蛋白磷酸酶 2A (PP2A) 在基因毒性应激后从 ATM 解离时，它会被共济失调毛细血管扩张突变 (ATM) 蛋白激酶激活。遗传毒性应激时 PP2A-C 从 ATM 中去除的机制尚未完全探索。此外，ATM/p53 通路在香烟烟雾诱导的细胞衰老和肺气肿发病机制中所起的作用仍然很大程度上未知。在这里，我们计划测试以下假设：脂筏蛋白 Caveolin-1 通过将 ATM 抑制剂 PP2A-C 封存在小凹中，促进 ATM 依赖性 p53 激活，从而介导应激诱导的过早衰老。此外，据推测，caveolin-1 通过诱导细胞衰老，在体内氧化剂促进的肺气肿中发挥着核心作用。该假设将通过追求三个具体目标来检验：具体目标 1：研究 Caveolin-1 在基因毒性应激后 PP2A 介导的 ATM 功能调节中的作用。具体目标 2：确定 Caveolin-1 表达缺失对 ATM 介导的 p53 激活和过早衰老的功能影响。具体目标 3：确定 Caveolin-1 在体内基因毒性应激诱导的肺气肿中的作用。这些研究将为将基因毒性应激与细胞衰老联系起来的信号机制提供新的见解，并提出将caveolin-1作为治疗肺气肿等年龄相关疾病的新治疗靶点。公共健康相关性：包括香烟烟雾在内的氧化应激会促进细胞过早衰老，这被认为在更复杂的衰老过程中发挥着重要作用，并导致肺气肿等与年龄相关的疾病。香烟烟雾诱发肺气肿的分子机制尚不完全清楚。我们的研究将检验这一假设，即蛋白质 Caveolin-1 是应激诱导的细胞衰老和肺气肿的新型调节剂，并提出 Caveolin-1 作为治疗肺气肿等年龄相关疾病的替代治疗靶点。