Childhood Cancer Gene Program Project Grant

儿童癌症基因计划项目资助

• 批准号: 6513026
• 负责人: JAMES R DOWNING
• 金额: $ 178.58万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-08-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6513026
• 关键词: molecular oncology; neoplasm /cancer genetics; pediatric neoplasm /cancer

The long-range goal of this program project is to improve our understanding of the pathogenesis and pathophysiology of childhood cancers, and to capitalize on the insights gained from these basic studies to device new means of assessing prognosis and improving therapy. This broad objective is being pursued through four interactive projects whose goal is to define the mechanisms by which chimeric transcription factors and altered tumor suppressors contribute to the pathogenesis of childhood cancer. Specifically, this program will examine the translocation-encoded fusion oncoprotein AML1-ETO and Pax3-FKHR and the ARF/Mdm2/p53 tumor suppressor pathway. Together, these genetic abnormalities represent the underlying lesions in a variety of common pediatric malignancies, including leukemias, soft tissue sarcomas, and epithelial tumors. The focus of Project 1 (M. Roussel) is to understand how p16/INK4a and ARF mediate tumor suppressive functions in different physiologic contexts, by studying their regulation, downstream targets and genetic modifier. Project 2 (J. Downing) seeks to define the molecular pathway by which alterations of AML1 leads to leukemia, by defining the spectrum of mutations that cooperate with the t(8;21)- encoded AML1-ETO oncoprotein to induce leukemia, and determine how point mutations in AML1 predispose hematopoietic stem cells to leukemic transformation. Project 3 (G. Grosveld) will use biochemical, cell biological and mouse experiments to determine how Pax3-FKHR acts as an activated oncogene in alveolar rhabdomyosarcoma, and to identify the secondary genetic alterations that are required to cooperate with Pax3-FKHR to induce a full tumor phenotype. In Project 4 (G. Zambetti) will directly examine the biochemical and biophysical properties of a novel germline p53 mutation (p53R337H) that has identified in a cluster of pediatric patients in Southern Brazil with adrenal cortical carcinoma (ACC). These patients lack features of Li-Fraumenia syndrome, suggesting that p53R337H is predisposing patients to ACC. To test this hypothesis, Dr. Zambetti will directly examine the biochemical and biophysical properties of this mutant p53 protein, and will develop mice that contain this mutation in the germline. The proposed research is supported by an Administrative Core and three scientific Core's that provide assistance in the generation of genetically modified mice and the subsequent analysis of these animals through a Pathology Core and a Microarray Gene Expression Laboratory. Through this coordinated program of research, we anticipate substantial progress toward the ultimate goal of improving the treatment of children with cancer.

该计划项目的长期目标是提高我们对儿童癌症发病机制和病理生理学的理解，并利用从这些基础研究中获得的见解来设计评估预后和改进治疗的新方法。这一广泛的目标是通过四个互动项目来实现的，这些项目的目标是确定嵌合转录因子和改变的肿瘤抑制因子在儿童癌症发病机制中的作用机制。具体地说，这个项目将研究易位编码的融合癌蛋白AML1-ETO和Pax3-FKHR以及ARF/MDM2/P53肿瘤抑制通路。总之，这些遗传异常代表了各种常见儿科恶性肿瘤的潜在损害，包括白血病、软组织肉瘤和上皮性肿瘤。项目1(M.Roussel)的重点是通过研究p16/INK4a和ARF的调控、下游靶点和遗传修饰来了解p16/INK4a和ARF如何在不同的生理环境中介导肿瘤抑制功能。项目2(J.Downing)试图通过定义与t(8；21)编码的AML1-ETO癌蛋白协同诱发白血病的突变谱来定义AML1改变导致白血病的分子途径，并确定AML1中的点突变如何使造血干细胞易于发生白血病转化。项目3(G.Grosveld)将使用生化、细胞生物学和小鼠实验来确定Pax3-FKHR如何在肺泡型横纹肌肉瘤中作为癌基因激活，并确定与Pax3-FKHR协同诱导完整肿瘤表型所需的继发性基因改变。在项目4中(G.Zambetti)将直接检测在巴西南部一群患有肾上腺皮质癌(ACC)的儿童患者中发现的一种新的胚系p53突变(P53R337H)的生化和生物物理特性。这些患者缺乏Li-Fraumenia综合征的特征，提示p53R337H是ACC的易感基因。为了验证这一假设，赞贝蒂博士将直接检查这种突变的P53蛋白的生化和生物物理特性，并将培育出在生殖系中包含这种突变的小鼠。拟议的研究得到一个行政核心和三个科学核心的支持，这两个核心通过一个病理学核心和一个微阵列基因表达实验室，在转基因小鼠的产生和随后对这些动物的分析方面提供帮助。通过这一协调的研究计划，我们预计将朝着改善儿童癌症治疗的最终目标取得实质性进展。