MOLECULAR BASIS OF RETINAL APOPTOSIS AND RETINOBLASTOMA

尽管在揭示细胞中的分子缺陷方面取得了显著进展， 遗传性视网膜变性和视网膜母细胞瘤， 这些情况仍不清楚。相同或相似的突变 光感受器基因可以产生多种临床疾病，包括 常染色体显性视网膜色素变性（RP）黄斑变性， RP扇区。rd和rds小鼠和RCS（rdy）中类似的视网膜变性 已经显示大鼠通过凋亡途径进行。此外，本发明还提供了一种方法， 表达人乳头瘤病毒E7蛋白的转基因小鼠（ 使视网膜母细胞瘤蛋白失活）， 细胞发生凋亡性视网膜变性而不是视网膜母细胞瘤。 该模型中的视网膜变性显示依赖于 存在功能性p53基因。这些和其他最近的结果表明， 在调节细胞存活的分子途径中可能存在重叠 和扩散。因此，拟议研究的目的是 研究导致视网膜变性的分子途径， 视网膜母细胞瘤在不同的小鼠模型。一些基因， 抑制凋亡（bcl-2和bcl-XL）或促进凋亡（bax和bcl-Xs） 最近被确认。bcl-2和bcl-XL的阻断能力 RD和RDS小鼠和转基因小鼠中的凋亡性视网膜变性 将通过产生转基因小鼠来测试在视网膜中表达E7的小鼠 在所述基因的控制下表达bcl-2或bcl-XL基因， 间质视黄醇结合蛋白（IRBP）启动子和杂交育种 这些小鼠与各种视网膜变性小鼠的区别。rd和rds小鼠 也将与缺乏功能性p53基因的小鼠杂交，以确定 这些模型中细胞凋亡对p53的依赖性。同样，老鼠 在IRBP的控制下表达SV 40 T抗原癌基因 启动子和发展成视网膜细胞瘤的小鼠将与小鼠杂交 表达IRBP-bax或IRBP-bcl-XS，以确定这些基因是否可以 抑制肿瘤发生。这些研究将回答几个问题。 重要问题：（1）表型明显的视网膜变性 由不同突变（rd与rds）引起的综合征是由共同的 凋亡途径？(2)细胞凋亡途径是否由 光感受器特异性基因的突变与 细胞周期控制中断引发的途径？(3)是bcl-2和 bax在感光细胞中的功能等同？(4)肿瘤发生 会被促进细胞凋亡的基因过度表达所阻断吗 最终，这些研究的结果可能会导致新的治疗方法 治疗这两种疾病的方法。

Despite remarkable progress in uncovering the molecular defects in inherited retinal degenerations and retinoblastoma, the pathogenesis of these conditions remains unclear. The same or similar mutations of photoreceptor genes can generate diverse clinical disorders, ranging from autosomal dominant retinitis pigmentosa (RP) to macular degeneration to sector RP. Similar retinal degenerations in rd and rds mice and RCS (rdy) rats have been shown to proceed by an apoptotic pathway. In addition, transgenic mice which express the human papillomavirus E7 protein (which inactivates the retinoblastoma protein) specifically in photoreceptor cells develop apoptotic retinal degeneration rather than retinoblastoma. The retinal degeneration in this model was shown to be dependent upon the presence of a functional p53 gene. These and other recent results suggest there may be overlap in the molecular pathways regulating cell survival and proliferation. Therefore, the purpose of the proposed research is to investigate the molecular pathways leading to retinal degeneration or retinoblastoma in the various mouse models. Several genes which either inhibit apoptosis (bcl-2 and bcl-XL) or promote apoptosis (bax and bcl-Xs) have recently been identified. The ability of bcl-2 and bcl-XL to block apoptotic retinal degeneration in rd and rds mice and in transgenic mice expressing E7 in the retina will be tested by producing transgenic mice expressing either the bcl-2 or bcl-XL gene under the control of the interstitial retinol-binding protein (IRBP) promoter and interbreeding these mice to the various retinal degeneration mice. The rd and rds mice will also be interbred to mice lacking a functional p53 gene to determine the dependence of apoptosis in those models upon p53. Similarly, mice expressing the SV40 T-Antigen oncogene under the control of the IRBP promoter and which develop retinoblastoma will be interbred with mice expressing IRBP-bax or IRBP-bcl-XS to determine whether these genes can suppress tumorigenesis. These studies will provide answers to several important questions: (1) Do phenotypically distinct retinal degeneration syndromes induced by different mutations (rd vs rds) result from a common pathway to apoptosis? (2) Does the apoptotic pathway(s) triggered by mutation of photoreceptor-specific genes share common elements with the pathway triggered by disruption of cell cycle control? (3) Are bcl-2 and bax functionally equivalent in photoreceptor cells? (4) Can tumorigenesis be blocked by the overexpression of genes that promote apoptosis? Ultimately, results from these studies may lead to novel therapeutic approaches for treatment of both of disorders.