GENE MAPPING AND ALLELIC ASSOCIATIONS WITH CANCER

基因图谱和等位基因与癌症的关联

• 批准号: 6123061
• 负责人: PAUL B SAMOLLOW
• 金额: $ 9.63万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6123061
• 关键词: alleles; animal genetic material tag; biochemical evolution; eye neoplasms; genetic markers; genetic models; genetic polymorphism; genome; linkage mapping; loss of heterozygosity; melanoma; neoplasm /cancer genetics; oncogenes; opossums; polymerase chain reaction; restriction fragment length polymorphism; southern blotting; tissue /cell culture; tumor suppressor genes

The long-term objectives are to establish a basic linkage map of the genome of the laboratory marsupial, Monodelphis domestica, and, thereby to increase the scientific value of this animal model in a variety of basic and applied research situations. The establishment of this gene map (the first for any marsupial) would enable the localization of genes that contribute to physiologically relevant variation in complex characteristics such as developmental anomalies and disease susceptibilities, and would provide additional insights regarding the evolution of the mammalian genome, particularly the conservation of gene syntony and linkage organization between Monodelphis and humans. This knowledge would facilitate the chromosomal localization and subsequent identification and molecular characterization of genes in the human genome that are possible homologs of genes that become identified as disease-related factors in the Monodelphis model. Our immediate plans are to utilize the gene map to identify associations between alleles at candidate tumor suppressor and oncogene loci and the occurrence of ultraviolet radiation-induced skin and eye neoplasia (melanocytic nevus, melanoma, and corneal sarcoma) that will be studied in Projects 1,2, and 3 of this Program Project. In the future we intend to use the map in concert with information generated in Projects 4 and 5 concerning the inheritance of variation in cholesterol metabolism, to localize and identify genes that affect differential lipemic responsiveness to high fat, high cholesterol dietary challenge. For the current project period, our aims are: 1) to generate a "framework map" composed of a minimum of 100 anonymous polymorphic DN marker sequences (using RAPD-PCR technology) in the Monodelphis genome, 2) to identify (via Southern blot/RFLP analysis) genetic polymorphisms among marsupial homologs of human tumor suppressor genes (APC, DCC, MCC, NF, p53, RB, WT) and ras family oncogenes (H-ras, K-ras, N-ras), 3) to establish the identities of linked gene clusters involving RAPD, tumor suppressor, oncogene, and (previously identified) isozyme loci via recombination analysis in multiply heterozygous female Monodelphis (which exhibit low recombination rates), 4) to initiate studies of gene order and linkage distances among synthetic marker loci using recombination data from multiply heterozygous males (which exhibit high recombination rates), 5) to identify associations between neoplastic phenotypes and particular alleles at tumor suppressor gene and oncogene loci, 6) to determine whether loss of heterozygosity (LOH) occurs at selected tumor suppressor loci in cultured cells derived from melanomas and corneal sarcomas of this species.

长期目标是建立一个基本的联系图， 基因组的实验室有袋动物，Monodelphis南极，因此， 以增加这种动物模型在各种领域的科学价值， 基础和应用研究情况。 这种基因的建立 一张地图（有袋动物的第一张地图）将使基因定位成为可能 这有助于复杂的生理相关变化， 发育异常和疾病等特征 能力，并将提供有关 哺乳动物基因组的进化，特别是基因的保守 与人之间的共振和连锁组织。 这 知识将有助于染色体定位和随后的 人类基因的鉴定和分子特征 基因组，这些基因可能是被鉴定为 Monodelphis模型中的疾病相关因素。 我们近期的计划是利用基因图谱来确定 在候选肿瘤抑制基因和癌基因位点的等位基因之间， 紫外线辐射引起的皮肤和眼睛肿瘤的发生 （黑色素细胞痣，黑色素瘤和角膜肉瘤），将进行研究 在本项目的项目1、2和3中。 在未来，我们打算 将地图与项目4中生成的信息结合使用， 5关于胆固醇代谢变异的遗传， 定位和鉴定影响差异脂血的基因 对高脂肪、高胆固醇饮食挑战的反应。 在目前的项目期间，我们的目标是：1）生成一个“框架 由至少100个匿名多态DN标记组成的”映射 序列（使用RAPD-PCR技术）在Monodelphis基因组，2）， 鉴定（通过Southern印迹/RFLP分析） 人肿瘤抑制基因（APC，DCC，MCC，NF， p53、RB、WT）和ras家族癌基因（H-ras、K-ras、N-ras），3）至 建立连锁基因簇的身份，涉及RAPD，肿瘤， 抑制基因、癌基因和（先前鉴定的）同工酶基因座， 在多杂合子雌性Monodelphis（ 表现出低重组率），4）启动基因顺序的研究 和使用重组的合成标记基因座之间的连锁距离 来自多杂合雄性（表现出高重组）的数据 率），5）确定肿瘤表型与 肿瘤抑制基因和癌基因位点的特定等位基因，6） 确定所选肿瘤是否发生杂合性缺失（洛） 来自黑色素瘤和角膜的培养细胞中的抑制基因座 该物种的肉瘤。