Canine Brain Tumors - A New Model for Gene Discovery

犬脑肿瘤——基因发现的新模型

• 批准号: 6900087
• 负责人: Matthew Breen
• 金额: $ 20.26万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6900087
• 关键词: animal genetic material tag; animal tissue; artificial chromosomes; bioinformatics; biotechnology; brain neoplasms; chromosome aberrations; comparative genomic hybridization; functional /structural genomics; genetic models; high throughput technology; human genetic material tag; microarray technology; model design /development; molecular oncology; neoplasm /cancer genetics

DESCRIPTION (provided by applicant): The NCI/NINDS Brain Tumor Progress Review Group (PRG) has highlighted that the available rodent model systems for brain tumors do not accurately represent the biology of human brain tumors. As a consequence the PRG has designated the development of new animal models as a high priority for research. We propose to investigate the molecular cytogenetics of spontaneous canine brain tumors, as a first step towards supporting the role of the domestic dog as a suitable animal model that will offer valuable insights into the genomics of brain neoplasia. Domestic dogs are organized into more than 350 phenotypically distinct genetic isolates ('breeds') characterized by unique constellations of morphology, behavior, and susceptibility to specific diseases, including cancers of the brain. Humans and dogs have similar physiology, share extensive genome homology with a high degree of preserved gene order, and are exposed to the same environment. Combined with the fact that the incidence and lifetime risk of naturally occurring brain tumors in dogs differ markedly between dog breeds, this offers a unique opportunity to identify molecular factors that define risk and prognosis. In previous studies, we have shown that evolutionarily conserved chromosome aberrations exist in human and canine hematopoetic cancers. Significantly, we also identified chromosomal aberrations in dogs for which corresponding changes have not been reported in humans. We hypothesize that these regions of the canine genome may contain cancer-associated genes that have thus far been intractable in studies of human families and tumors due to the genetic 'noise' present in human populations. Our long-term goals are to identify genetic lesions that account for the origin of brain cancers and that influence disease progression and prognosis. For this project, we propose to utilize the emerging canine genome assembly to select a panel of 3,000 BAG clones and generate a genome-wide microarray with 1Mb resolution. We will then conduct array-based comparative genomic hybridization (array-CGH) analysis of 50 canine brain tumors as a means by which to identify recurrent regions of copy number change. Comparative bioinformatics will be used to identify genes located within these regions of genomic imbalance that warrant further investigation. Characterization of these genetic loci will help to improve the definition of molecular risk and prognosis of human and canine brain tumors, with a potentially major impact on human health.

描述（由申请人提供）：NCI/NINDS脑肿瘤进展审查小组（PRG）强调，现有的脑肿瘤啮齿动物模型系统不能准确代表人类脑肿瘤的生物学。因此，PRG已将新动物模型的开发指定为研究的重中之重。我们建议研究自发性犬脑肿瘤的分子细胞遗传学，作为支持家犬作为合适的动物模型的作用的第一步，这将为脑肿瘤的基因组学提供有价值的见解。家犬被组织成350多个表型不同的遗传分离物（“品种”），其特征在于独特的形态，行为和对特定疾病（包括脑癌）的易感性。人类和狗具有相似的生理机能，具有广泛的基因组同源性和高度保存的基因顺序，并且暴露于相同的环境。结合犬中自然发生的脑肿瘤的发病率和终生风险在犬种之间存在显著差异的事实，这为确定定义风险和预后的分子因素提供了独特的机会。在以前的研究中，我们已经表明，进化保守的染色体畸变存在于人类和犬造血癌。值得注意的是，我们还在犬中发现了染色体畸变，而在人类中未报告相应的变化。我们假设，这些区域的犬基因组可能包含癌症相关基因，迄今为止，由于人类群体中存在的遗传“噪音”，在人类家族和肿瘤的研究中一直难以解决。我们的长期目标是确定导致脑癌起源并影响疾病进展和预后的遗传病变。对于这个项目，我们建议利用新兴的犬基因组组装选择一组3,000 BAG克隆，并产生一个全基因组的微阵列与1 Mb的分辨率。然后，我们将对50个犬脑肿瘤进行基于阵列的比较基因组杂交（阵列CGH）分析，作为识别拷贝数变化的复发区域的方法。比较生物信息学将用于确定位于这些基因组不平衡区域内的基因，这些基因组不平衡区域需要进一步研究。这些基因位点的表征将有助于改善人类和犬脑肿瘤的分子风险和预后的定义，对人类健康具有潜在的重大影响。