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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生物体水平的损伤累积。遗传毒性应激在衰老和与年龄相关的疾病如肺气肿中起着重要作用，肺气肿是由持续氧化应激后肺维持和修复失败引起的。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。过早衰老被认为有助于遗传毒性应激诱导的肺气肿。肿瘤抑制蛋白p53是早衰的关键调节因子，并且当遗传毒性应激后ATM抑制蛋白磷酸酶2A（PP 2A）从ATM解离时，由共济失调-毛细血管扩张突变（ATM）蛋白激酶激活。PP 2A-C在遗传毒性胁迫下从ATM中去除的潜在机制仍然完全未被探索。此外，ATM/p53通路在香烟烟雾诱导的细胞衰老和肺气肿的发病机制中所起的作用在很大程度上仍然未知。在这里，我们计划测试的假设，脂筏蛋白小窝蛋白-1介导的压力诱导的早衰，通过促进ATM依赖性激活p53通过螯合的ATM抑制剂PP 2A-C到小窝。此外，假设小窝蛋白-1通过诱导细胞衰老在体内氧化剂促进的肺气肿中起核心作用。这一假设将通过追求三个具体目标进行测试：具体目标1：研究基因毒性应激后小窝蛋白-1在PP 2A介导的ATM功能调节中的作用。具体目标2：确定小窝蛋白-1表达的丧失对ATM介导的p53激活和早衰的功能后果。具体目标3：确定小窝蛋白-1在体内遗传毒性应激诱导的肺气肿中的作用。这些研究将为将遗传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caveolin-1作为治疗年龄相关疾病（如肺气肿）的新治疗靶点。公共卫生关系：氧化应激，包括吸烟，促进细胞过早衰老，这被认为在更复杂的衰老过程中起重要作用，并导致与年龄相关的疾病，如肺气肿。香烟烟雾诱发肺气肿的分子机制尚未完全清楚。我们的研究将测试的假设，即蛋白质小窝蛋白-1是一种新的调节应激诱导的细胞衰老和肺气肿，并提出小窝蛋白-1作为一种替代的治疗目标，用于治疗与年龄有关的疾病，如肺气肿。