GENOMICS OF APOPTOSIS & ANGIOGENESIS IN ISLET CARCINOMA

癌症的转基因小鼠模型呈现出一系列实验性 机会，包括阐明肿瘤发展的途径 和进步。 与人类癌症一样，在小鼠 肿瘤的发生有可能是有指导意义的机制， 导致癌症的潜在途径 在过去的十年里， 胰岛细胞癌模型已被证明是一个有价值的原型， 研究多阶段肿瘤发生的参数。 具体变化 包括杂合性/DNA拷贝数特征性丢失， 染色体9（命名为LOH9）和16（LOH16），获得 抗凋亡和诱导血管生成。 这些 观察导致LOH9编码细胞凋亡的假设， LOH16编码血管生成抑制基因。 这 该项目汇集了哈纳汉实验室的互补人才， 拥有转基因小鼠模型及其 和格雷实验室，他们在癌症方面有专业知识， 遗传学和表征癌细胞基因组的技术。 这些实验将一起精确地确定最小程度的 LOH9和LOH16，检验细胞凋亡和血管生成是 部分由这些区域的肿瘤抑制基因控制， 鉴定所涉及的基因，分别命名为loh 9和loh 16。 在这样做的过程中，该项目将阐明 肿瘤发生在这个模型中，并有助于发展和完善 这些技术策略应该被证明广泛适用于鼠标 癌症模型。 具体而言，该项目将： 筛选技术来检测和精细结构映射这些肿瘤 利用多重洛缺失和基于阵列的CGH的抑制基因座，和 在对一个银行的分析过程中， 大约450例胰岛癌;评估LOH 9的假设 LOH16编码一个凋亡调节基因， 抑制血管生成，使用体外和体内生物测定， 结合基因组分析、功能选择和遗传学 通过BAC DNA转移进行互补; 功能互补和/或定位克隆技术，和 开始分析它们在胰岛癌中的表达及作用 途径，以及人类癌症。

Transgenic mouse models of cancer present a spectrum of experimental opportunities, including elucidation of pathways of tumor development and progression. As in human cancers, genetic changes during mouse tumorigenesis have the potential to be instructive about mechanisms underlying pathways to cancer. Over the last decade the RIP-Tag mouse model of islet cell carcinoma has proved a valuable prototype for investigating parameters of multistage tumorigenesis. Specific changes include characteristic losses of heterozygosity/DNA copy number on chromosomes 9 (designated LOH9) and 16 (LOH16), acquisition of resistance to apoptosis, and induction of angiogenesis. These observations have lead to the hypothesis that LOH9 encodes an apoptosis regulatory gene and LOH16 encodes an angiogenesis suppressor gene. This project brings together complementary talents of the Hanahan lab, which has expertise and experience in transgenic mouse models and their characterization, and the Gray lab, which has expertise in cancer genetics and in technologies for characterizing cancer cell genomes. Together these labs shall precisely determine the minimal extents of LOH9 and LOH16, test the hypothesis that apoptosis and angiogenesis are partly controlled by tumor suppressor genes in these regions and identify the involved genes, designated loh9 and loh16; respectively. In so doing, this project will shed light on the mechanism of tumorigenesis in this model, and serve to develop and refine technological strategies that should prove broadly applicable to mouse models of cancer. Specifically, this project will: Develop genome screening technologies to detect and fine structure map these tumor suppressor loci utilizing multiplex LOH and array-based CGH, and rigorously compare these techniques during the analysis of a bank of approximately 450 islet carcinomas; Assess the hypotheses that LOH9 encodes an apoptosis regulatory gene and that LOH16 encodes a gene that suppresses angiogenesis, using in vitro and in vivo bioassays in conjunction with genomic analysis, functional selection, and genetic complementation via BAC DNA transfer; Isolate loh9 and loh16 using functional complementation and/or positional cloning techniques, and begin to analyze their expression and roles in the islet carcinoma pathway, and in human cancers.