GENOMICS OF APOPTOSIS & ANGIOGENESIS IN ISLET CARCINOMA

癌症转基因小鼠模型呈现出一系列实验结果 机会，包括阐明肿瘤发展的途径 和进展。 与人类癌症一样，小鼠体内的基因发生变化 肿瘤发生有可能对机制具有指导意义 癌症的潜在途径。 过去十年中 RIP-Tag 鼠标 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 拷贝数的特征损失 9 号染色体（指定为 LOH9）和 16 号染色体（LOH16），获得 抗细胞凋亡和诱导血管生成。 这些 观察结果得出 LOH9 编码细胞凋亡的假设 LOH16 编码血管生成抑制基因。 这个 该项目汇集了 Hanahan 实验室的互补人才， 在转基因小鼠模型及其研究方面拥有专业知识和经验 表征以及拥有癌症专业知识的格雷实验室 遗传学和表征癌细胞基因组的技术。 这些实验室将共同精确地确定最小范围 LOH9 和 LOH16，检验细胞凋亡和血管生成是相关的假设 部分由这些区域的肿瘤抑制基因控制 确定所涉及的基因，指定为 loh9 和 loh16；分别。 在此过程中，该项目将阐明 该模型中的肿瘤发生，并用于开发和完善 应该证明广泛适用于鼠标的技术策略 癌症模型。 具体来说，该项目将： 开发基因组 检测这些肿瘤并绘制精细结构图的筛选技术 利用多重 LOH 和基于阵列的 CGH 的抑制位点，以及 在分析银行的过程中严格比较这些技术 大约 450 个胰岛癌； 评估 LOH9 的假设 LOH16 编码一个凋亡调节基因，并且 LOH16 编码一个基因 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 通过 BAC DNA 转移进行互补； 使用隔离 loh9 和 loh16 功能互补和/或定位克隆技术，以及 开始分析它们在胰岛癌中的表达和作用 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.