p53 and Chemosensitivity in a Mouse Lymphoma Model

小鼠淋巴瘤模型中的 p53 和化疗敏感性

• 批准号: 7112857
• 负责人: SCOTT W. LOWE
• 金额: $ 33.04万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7112857
• 关键词: B cell lymphoma; apoptosis; biological signal transduction; bone marrow transplantation; cell growth regulation; cell senescence; disease /disorder model; drug resistance; genetically modified animals; high throughput technology; laboratory mouse; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neoplastic cell; p53 gene /protein; pharmacogenetics; phosphatidylinositol 3 kinase

p53 acts in a complex tumor suppressor network that mediates cellular responses to stress. Thus, p53 is activated in response to diverse cellular insults, including mitogenic oncogenes, hypoxia, oxidative stress, and DNA damage. Once activated, p53 can trigger a variety of anti-proliferative programs, including apoptosis and cellular senescence, by targeting multiple components of each program's effector machineries. Since many of the chemotherapeutic agents currently used to treat cancer directly or indirectly damage DNA, they often rely on the integrity of the p53 pathway to elicit their anti-tumor effects. As a consequence, drug resistance can arise as a byproduct of tumor evolution. This project is interested in how p53 modulates the action of conventional and targeted drugs, and the implications of disrupting the p53 network at different points from tumor evolution to drug resistance. To study these processes, we use the E-mu-myc transgenic model of B-cell lymphoma as a tractable yet physiological test system. Over the last funding period, we developed methods to rapidly produce lymphomas with complex genotypes, and then study the impact of these lesions on tumor cell responses to therapy using approaches that parallel clinical trials. Using this system, we identified a number of biological (apoptosis, senescence, translational control) and genetic (p53, ARF, INK4a/ARF, Bcl-2, Akt, elF4E) determinants of drug action. In the current proposal, we will continue to study components of the p53 network that influence apoptosis and senescence for their impact on chemosensitivity, and will examine how survival signaling through the PI3kinase/Akt network affects p53 action to promote chemoresistance. However, we also will initiate efforts to explore the utility of the E-mu-myc system to study new drugs, in particular, by testing strategies to reverse chemoresistance in vivo. Furthermore, we will exploit the unique features of the E-mu-myc model to conduct high throughput screens to identify new genes that influence treatment responses in vivo. We expect that our results will produce a better understanding of the p53 and Akt networks and how they influence drug sensitivity and resistance in vivo. By understanding mechanisms of drug resistance and testing strategies to circumvent it, we may identify new therapeutic targets or treatment strategies that can be extended to clinical trials.

p53在介导细胞对应激的反应的复杂肿瘤抑制网络中起作用。因此，p53是 响应于不同的细胞损伤而被激活，包括促有丝分裂癌基因、缺氧、氧化应激， 和DNA损伤一旦激活，p53可以触发多种抗增殖程序，包括 细胞凋亡和细胞衰老，通过靶向每个程序的效应器的多个组件 机械。由于目前用于直接或间接治疗癌症的许多化学治疗剂 由于它们破坏DNA，它们通常依赖于p53通路的完整性来引发其抗肿瘤作用。作为 因此，耐药性可能作为肿瘤演变的副产品而出现。这个项目关注的是 p53调节常规和靶向药物的作用，以及破坏p53的意义 从肿瘤演变到耐药性的不同点。为了研究这些过程，我们使用 B细胞淋巴瘤的E-mu-myc转基因模型作为一个易处理的生理测试系统。在过去 在资助期间，我们开发了快速产生具有复杂基因型的淋巴瘤的方法，然后 研究这些病变对肿瘤细胞对治疗反应的影响， 审判使用这个系统，我们确定了一些生物（细胞凋亡，衰老，翻译控制） 和药物作用的遗传（p53、ARF、INK 4a/ARF、Bcl-2、Akt、eIF 4 E）决定因素。在目前的提案中， 我们将继续研究p53网络中影响凋亡和衰老的成分， 对化疗敏感性的影响，并将研究如何通过PI 3激酶/Akt网络的生存信号 影响p53作用以促进化学抗性。然而，我们也将努力探索 E-mu-myc系统研究新药，特别是通过测试逆转化疗耐药性的策略， vivo.此外，我们将利用E-mu-myc模型的独特功能进行高通量的研究。 筛选以鉴定影响体内治疗反应的新基因。我们希望我们的结果 更好地了解p53和Akt网络以及它们如何影响药物敏感性， 体内抗性。通过了解耐药性机制和测试规避耐药性的策略， 我们可以确定新的治疗靶点或治疗策略，并将其扩展到临床试验。