Building better animal models of prostate cancer

建立更好的前列腺癌动物模型

• 批准号: 6556055
• 负责人: MILTON W DATTA
• 金额: $ 14.6万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-07 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6556055
• 关键词: biomarker; carcinogenesis; disease /disorder model; genetic mapping; genetic susceptibility; laboratory rat; male; metastasis; microarray technology; model design /development; neoplasm /cancer genetics; prostate neoplasms

DESCRIPTION (provided by applicant): Research in prostate cancer has been hampered by the lack of applicable animal models that reflect both the clinical and biologic behavior of human prostate cancer,in particular its metastatic potential. With genomic information available for human and animal models it may be possible to develop new models that match the clinical and biologic phenotype. Technologies are now available that allow the transfer of portions of the genome ranging from whole or partial chromosomes (consomic or congenic animals) to individual genes (producing animals by transgenicor homologous recombination technologies). What these technologies need are the defined genomic regions that characterize the clinical and pathologic basis of prostate cancer. The starting point would include a model of hormonally modulated tumors that spontaneously develop with age and which metastasize. The Lobund-Wistar rat is the only example of spontaneous metastasizing androgen-modulated neoplasia and will be used to initiate the development of a better model. We are encouraged that this may be possible; because of a preliminary genome sharing analysis suggest that the chromosoaml regiona involved in the Lobund-Wistar rat are syntenic to regions involved in human prostate cancer. Thus the Lobund-Wistar rat has features that match the clinical and potentially the genomic basis of human prostate cancer. By defining the genetic region(s) associated with the features common to human prostate cancer we propose to create susceptibility regions, that by virtue of comparative mapping could be used in either mouse or rat systems to engineer better animal models of human prostate cancer. Here we propose the studies necessary to validate and extend the identified chromosomal regions through genetic crosses. In addition, in order to shorten the interval to phenotypic evaluation we propose to develop a better phenotypic biomarker for early disease. The use of global gene expression patterns as an intermediate biomarker for subsequent tumor formation and metastasis would provide a unique fingerprint that could be evaluated in younger animals, thereby reducing the time to phenotypic analysis. We will develop an expression fingerprint that correlates with tumor formation using expression microarray technology and utilize this pattern as a phenotype in future evaluation of Lobund-Wistar rats. These studies are essential in the development of new animal models of prostate cancer.

描述（由申请人提供）：缺乏反映人类前列腺癌的临床和生物学行为的适用动物模型，尤其是其转移性潜力，因此阻碍了前列腺癌的研究。借助可用于人类和动物模型的基因组信息，可以开发与临床和生物学表型相匹配的新模型。现在可以使用技术，可以转移从整体或部分染色体（辅助或同类动物）到单个基因（通过转基因同源重组技术产生动物）的基因组部分。这些技术需要的是定义的基因组区域，这些区域是前列腺癌的临床和病理基础的特征。起点将包括一种荷尔蒙调制的肿瘤模型，该模型随着年龄的增长和转移而自发发展。 Lobund-Wistar大鼠是自发转移雄激素调节的肿瘤的唯一例子，将用于启动更好的模型的发展。鼓励我们可能有可能；由于初步的基因组共享分析表明，参与洛邦 - 威斯塔尔大鼠的染色体区域与参与人类前列腺癌的区域同步。因此，Lobund-Wistar大鼠的特征与人类前列腺癌的临床和基因组基础相匹配。通过定义与人类前列腺癌常见的特征相关的遗传区域，我们建议创建易感区域，根据比较映射，可以在小鼠或大鼠系统中使用比较映射，以设计更好的人类前列腺癌动物模型。在这里，我们提出了通过遗传杂交验证和扩展所确定的染色体区域所需的研究。此外，为了缩短表型评估的间隔，我们建议为早期疾病开发更好的表型生物标志物。将全球基因表达模式用作随后的肿瘤形成和转移的中间生物标志物，将提供一种独特的指纹，可以在年轻动物中进行评估，从而减少了表型分析的时间。我们将开发一种表达指纹，该指纹与表达微阵列技术与肿瘤形成相关，并将这种模式用作未来对洛邦 - 威斯塔尔大鼠的表型。这些研究对前列腺癌的新动物模型的发展至关重要。