RB PROTEIN INACTIVATION IN THE RETINA OF TRANSGENIC MICE

视网膜母细胞瘤是一种眼部恶性肿瘤， 孩子 这种疾病已被证明是由于失活的 视网膜母细胞瘤易感基因Rb的等位基因。 的 一位首席研究员先前描述了一种转基因品系， 通过癌基因介导的视网膜母细胞瘤失活的小鼠 视网膜细胞中Rb基因产物pRb。 这些老鼠提供了 第一个可遗传的视网膜母细胞瘤动物模型系统。 建议进一步研究其作用机制， 视网膜母细胞瘤的形成。 具体来说， 额外的突变事件涉及基因重排或 癌基因扩增将被解决，使用细胞系来源于 原发性视网膜母细胞瘤。 将产生另外的转基因小鼠品系，其中pRb和pRb基因均表达。 和另一种生长抑制基因产物p53， 特定的视网膜细胞，这些小鼠将与小鼠交配， 在相同的视网膜细胞中过表达pRb，以测试pRb 失活足以形成视网膜母细胞瘤。 另外， 将产生在视网膜中失活的pRb而不是p53，并且 视网膜母细胞瘤形成的发生率将与 两种蛋白质都失活的小鼠，以评估参与 p53在肿瘤形成中的作用 最后，在pRb和p53两者或仅一者或另一者均表达的小鼠中， 将在成骨细胞中灭活，以测试这些 成视网膜细胞瘤中常见的继发性肿瘤骨肉瘤蛋白 患者 这些研究旨在评估模型， 视网膜是唯一易受肿瘤发生的， 需要灭活，而其他组织中的肿瘤形成 需要额外的突变事件

Retinoblastoma is a malignancy of the eye primarily afflicting young children. This disease has been shown to result from inactivation of both alleles of the retinoblastoma susceptibility gene, Rb. The principal investigator has previously described a line of transgenic mice which develop retinoblastoma via oncogene-mediated inactivation of the Rb gene product, pRb, in retinal cells. These mice provided the first heritable animal model system for retinoblastoma. Studies are proposed to further investigate the mechanism of retinoblastoma formation in these mice. Specifically, the possibility that additional mutational events involving gene rearrangements or oncogene amplification will be addressed, using cell lines derived from primary retinoblastoma tumors in these mice. Additional lines of transgenic mice will be produced in which both pRb and another growth suppressor gene product, p53, are inactivated in specific retinal cells, and these mice will be mated to mice overexpressing pRb in the same retinal cells to test the model that pRb inactivation is sufficient for retinoblastoma formation. Also, mice in which pRb but not p53 is inactivated in tbe retina will be produced, and the incidence of retinoblastoma formation will be compared to that of mice in which both proteins are inactivated, to assess the involvement of p53 in the formation of this tumor. Finally, mice in which both pRb and p53 or only one or the other are inactivated in osteoblasts will be produced to test the role of these proteins in osteosarcoma, a common second tumor in retinoblastoma patients. These studies are designed to evaluate the model that the retina is uniquely susceptible to tumorigenesis in that only pRb inactivation is required, while tumor formation in other tissues requires additional mutation events.