MOLECULAR BASIS OF RETINAL APOPTOSIS AND RETINOBLASTOMA

尽管在发现分子缺陷方面取得了显著进展，但 遗传性视网膜变性和视网膜母细胞瘤的发病机制 这些条件仍不明朗。相同或相似的突变 光感受器基因可导致多种临床疾病，范围从 常染色体显性遗传性视网膜色素变性(RP)至黄斑变性 扇区RP。RD和RDS小鼠以及RCS(Rdy)中类似的视网膜变性 大鼠已被证明是通过一条凋亡途径进行的。此外, 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)，特别是在光感受器 细胞发生凋亡性视网膜变性，而不是视网膜母细胞瘤。 在这个模型中，视网膜的退化被证明依赖于 存在功能正常的P53基因。这些和其他最近的结果表明 调节细胞存活的分子通路可能存在重叠。 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或 各种小鼠模型中的视网膜母细胞瘤。几个基因要么是 抑制细胞凋亡(BCL-2和BCL-XL)或促进细胞凋亡(Bax和BCL-Xs) 最近都被确认了。BCL-2和BCL-XL的阻断能力 RD和RDS小鼠及转基因小鼠的凋亡性视网膜变性 将通过生产转基因小鼠来测试在视网膜中表达E7的情况 BCL-2或BCL-XL基因的表达 间质视黄醇结合蛋白启动子与杂交 这些小鼠给各种视网膜变性小鼠。RD和RDS小鼠 也会与缺乏功能性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。类似地，老鼠 在IRBP控制下表达SV40T-抗原癌基因 将启动子和发生视网膜母细胞瘤的启动子与小鼠杂交 表达IRBP-BAX或IRBP-BCL-XS以确定这些基因是否可以 抑制肿瘤的发生。这些研究将为以下几个问题提供答案 重要问题：(1)是否存在明显的视网膜变性 由不同突变(RD与RD)引起的综合征是由共同的 细胞凋亡途径？(2)细胞凋亡途径(S)是否被 光感受器特异基因的突变与 细胞周期调控中断所触发的信号转导途径？(3)bcl2和 光感受器细胞中Bax功能等同？(4)肿瘤发生 会不会被促进细胞凋亡的基因过度表达所阻断？ 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.