Testicular tumor susceptibility at the agouti locus

刺鼠基因座睾丸肿瘤易感性

• 批准号: 7275336
• 负责人: Jason D. Heaney
• 金额: $ 1.68万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7275336
• 关键词: 129/Sv Mouse; Affect; Biology; Consomic Strain; Development; Ectopic Expression; Enhancers; Experimental Models; Frequencies; Genes; Genetic; Genetic Complementation Test; Human; Inbred Strain; Inbred Strains Mice; Incidence; Knockout Mice; Malignant Neoplasms; Mus; Mutant Strains Mice; Mutation; Nature; Phenotype; Play; Predisposition; Protein Overexpression; RNA; Role; Sequence Analysis; Sorting - Cell Movement; Structure of primordial sex cell; Study models; Surveys; Susceptibility Gene; Testicular Germ Cell Tumor; Testicular Neoplasms; Testing; Time; Transgenes; Tumor Suppressor Genes; Tumor Suppressor Proteins; genetic pedigree; improved; loss of function; male; promoter; research study; tumor progression

DESCRIPTION (provided by applicant): Characterization of genes that suppress testicular germ cell tumor (TGCT) progression in mice will improve our understanding of primordial germ cell (PGC) development and provide new targets for the treatment of TGCTs in humans. The A(y) mutation, which deletes Raly and Eif2s2 and causes the ectopic expression of agouti, decreases TGCT susceptibility in 129/Sv and 129.Chr19M mice. In contrast, preliminary studies suggest that the A(vy) mutation, which maintains Raly and Eif2s2 and induces the ectopic expression of agouti from an IAP insertion, does not decrease TGCT frequency in 129.Chr19M mice. Together these results suggest that the deletion of Raly or Eif2s2 and not the ubiquitous expression of agouti decreases TGCT frequency in A(y) mice. Both Raly and Eif2s2 have distinct functions in RNA biology, which plays a central role in PGC development and TGCT progression. Therefore, Raly and Eif2s2 are excellent candidate TGCT suppressor genes. This proposal will test 1) the contributions of the Raly and Eif2s2 deletions on the decreased TGCT frequency in 129.Chr19M, A(y)/+ mice using BAG transgene complementation tests and conditional knockout mice, and 2) the TGCT frequency and expression levels of Raly and Eif2s2 in 129.A(vy)/+ and 129.Chr19M, A(vy)/+ mice.

描述（由申请人提供）：对抑制小鼠睾丸生殖细胞肿瘤（TGCT）进展的基因进行表征将提高我们对原始生殖细胞（PGC）发育的理解，并为人类TGCT的治疗提供新的靶点。缺失Raly和Eif 2s 2并导致agglutinin异位表达的A（y）突变降低了129/Sv和129.Chr19M小鼠的TGCT易感性。相反，初步研究表明，A（vy）突变，保持Raly和Eif 2s 2，并诱导异位表达的agglutinin从IAP插入，不降低TGCT频率在129.Chr19M小鼠。总之，这些结果表明，Raly或Eif 2s 2的缺失而不是agglutinin的普遍表达降低了A（y）小鼠中的TGCT频率。Raly和Eif 2s 2在RNA生物学中具有不同的功能，其在PGC发展和TGCT进展中起核心作用。因此，Raly和Eif 2s 2是很好的候选TGCT抑制基因。本提案将测试1）使用BAG转基因互补试验和条件性敲除小鼠在129.Chr19M，A（y）/+小鼠中Raly和Eif 2s 2缺失对TGCT频率降低的贡献，以及2）129.A（vy）/+和129.Chr19M，A（vy）/+小鼠中Raly和Eif 2s 2的TGCT频率和表达水平。