Quantitative Proteomic Analysis of the Secretory Pattern of Senescent Cells

衰老细胞分泌模式的定量蛋白质组学分析

• 批准号: 7187525
• 负责人: YUZURU SHIIO
• 金额: $ 14.97万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-15 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7187525
• 关键词: Affect; Affinity; Age; Aging; Aging-Related Process; Applications Grants; Architecture; Arterial Fatty Streak; Biological Models; Cell Aging; Cells; Characteristics; Code; Cultured Cells; Disease; Endothelial Cells; Epithelial Cells; Fibroblasts; Future; Genes; Human; In Vitro; Investigation; Isotopes; Isotopically-Coded Affinity Tagging; Knowledge; Lesion; Longevity; Malignant Neoplasms; Mediating; Messenger RNA; Methods; NIH Program Announcements; Neoplastic Epithelial Cell; Normal Cell; Numbers; Oncogenic; Pathology; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Prevention; Protein Secretion; Proteins; Proteomics; Research Personnel; Site; Stimulus; Technology; Testing; Tissues; Tumor Cell Line; age related; base; cell type; in vivo; mRNA Expression; neoplastic cell; novel; outcome forecast; programs; ras Oncogene; response; senescence; tumor

DESCRIPTION (provided by applicant): Proliferative senescence of cultured cells is a useful model system to study aging in vitro. In vivo, senescent cells accumulate in aging tissues and at sites of age-related pathologies such as atherosclerotic lesions and preneoplastic lesions, raising the possibility that senescent cells may promote the aging phenotype or age-related pathologies. Indeed, senescent cells were shown to secrete proteins that can alter the function and architecture of the surrounding tissues. In addition to normal cells, tumor cells also undergo proliferative senescence upon treatment with chemotherapeutic drugs. Importantly, many genes that are induced in senescent tumor cells encode secreted proteins with both tumor-promoting and tumor-suppressing activities, which can affect the prognosis of tumor patients. Therefore, the emerging hypothesis is that protein secretion from senescent cells mediates the in vivo aging process and age-related pathologies, as well as the tumor response to therapy. In this context, it is important to note that only a small number of studies have been carried out on proteins secreted from senescent cells and that we still lack comprehensive knowledge of the secretory patterns of normal as well as tumor cells undergoing senescence. Employing a novel quantitative proteomics technology, ICAT (isotope-coded affinity tag), we have developed a method to systematically identify and quantify proteins secreted in culture supernatant, and using this method, we analyzed the secretory pattern of human fibroblasts undergoing replicative senescence. We propose to extend this analysis by 1) comparing the secretory patterns of senescent fibroblasts induced to senesce by different mechanisms, by 2) comparing the secretory patterns of senescent fibroblasts and senescent endothelial cells, and by 3) analyzing the secretory patterns of tumor cells induced to senesce by chemotherapeutic drug treatment. The secretory patterns of senescent cells identified through this exploratory project will provide a basis for future investigations on the fundamental principles governing aging processes as well as more effective treatment and prevention of age-related diseases and cancer.

描述（由申请人提供）：培养细胞的增殖性衰老是一种在体外研究衰老的有用模型系统。在体内，衰老细胞积聚在衰老的组织和年龄相关病理（例如动脉粥样硬化病变和前肿瘤病变）的部位，从而增加了衰老细胞可以促进衰老表型或与年龄相关的病理学的可能性。实际上，衰老细胞被证明可以分泌可以改变周围组织功能和结构的蛋白质。除正常细胞外，肿瘤细胞在化学治疗药物治疗后还会经历增生性衰老。重要的是，在衰老肿瘤细胞中诱导的许多基因用肿瘤促进和肿瘤抑制活性编码分泌的蛋白质，这可能影响肿瘤患者的预后。因此，新出现的假设是，衰老细胞的蛋白质分泌介导体内衰老过程和与年龄相关的病理以及肿瘤对治疗的反应。在这种情况下，重要的是要注意，仅对衰老细胞分泌的蛋白质进行了少量研究，并且我们仍然缺乏对正常和肿瘤细胞的分泌模式的全面了解。我们采用了一种新型的定量蛋白质组学技术（同位素编码的亲和力标签），我们开发了一种方法来系统地识别和量化培养上清液中分泌的蛋白质，并使用这种方法，分析了人类成纤维细胞的分泌模式，这些模式受到了重复的衰老。我们建议通过1）将这种分析扩展到通过不同机制诱导的衰老成纤维细胞的分泌模式，2）比较2）比较衰老成纤维细胞和衰老内皮细胞的分泌模式，以及3）分析通过化学药物诱导的肿瘤细胞的分析模式。通过该探索性项目确定的衰老细胞的分泌模式将为未来研究有关老化过程的基本原则以及对年龄相关疾病和癌症的更有效治疗和预防的基本原理提供基础。