RB PROTEIN INACTIVATION IN THE RETINA OF TRANSGENIC MICE

视网膜母细胞瘤是一种主要影响年轻人的眼部恶性肿瘤。 孩子们。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的两个等位基因。这个 首席研究员此前曾描述过一种转基因 癌基因介导的小鼠视网膜母细胞瘤的失活 视网膜细胞中的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。 建议进行研究，以进一步研究其作用机制。 这些小鼠视网膜母细胞瘤的形成。具体地说，有可能 其他涉及基因重排的突变事件或 癌基因扩增将使用来自于 这些小鼠的原发视网膜母细胞瘤。 将产生额外的转基因小鼠品系，在这些品系中， 而另一种生长抑制基因产物，P53，在 特定的视网膜细胞，这些小鼠将与小鼠交配 在同一视网膜细胞中过表达pRb以检验pRb模型 失活足以形成视网膜母细胞瘤。此外，老鼠在 视网膜中会产生哪种pRb而不是p53被灭活，以及 视网膜母细胞瘤形成的发生率将与 两种蛋白都失活的小鼠，以评估参与 P53在肿瘤形成中的作用。 最后，在pRb和p53都或只有其中之一的小鼠中 将产生失活的成骨细胞来测试这些作用 视网膜母细胞瘤中常见的继发肿瘤骨肉瘤中的蛋白质 病人。这些研究旨在评估以下模型： 视网膜对肿瘤的发生特别敏感，因为只有PRB 需要灭活，而在其他组织中形成肿瘤 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.