Genetic Mechanisms of Retinal Degenerative Disease

描述(申请人提供)：视网膜色素变性是一组 遗传性视网膜变性影响50,000至100,000人 美国。在过去的十年里，在确定 致病基因突变。然而，人们对此知之甚少 这些突变触发光感受器细胞死亡的机制，使 开发有效的治疗方法很困难。这些措施的长期目标是 研究的目的是确定光感受器细胞死亡的分子触发因素。 具体地说，这些研究将检验这样一个假设，即基因突变 影响视紫红质信号转导效率的物质会导致视网膜变性。 将测试转导信号在视网膜退行性疾病中的作用 使用敲除杆状基因的信号缺陷转基因小鼠 α转导蛋白基因。这些小鼠将被用来测试两个拟议的特定 目标。特殊目标1将测试一些视紫红质突变的假设 通过结构性激活转导信号而导致变性，类似于 持续光照对啮齿动物视网膜的损伤。特定目标 2将检验这样一种假设，即视蛋白载脂蛋白可能随着 视紫红质再生有缺陷，会产生导致退化的信号。 为了实现这些目标，视紫红质突变小鼠和产生视蛋白的转基因小鼠 小鼠将被杂交到转导基因敲除小鼠。《特定目标3》将测试 假设视紫红质密度增加或减少，这会影响 视紫红质信号的效率，导致视网膜退化。级别 维持正常视网膜形态所需的视紫红质，此时 视紫红质必须表达，以挽救变性，以及如何增加水平 视紫红质突变背景下的野生型视紫红质影响 视网膜变性将被定义。具体目标3将通过以下方式实现 药物诱导视紫红质表达的转基因小鼠。这些研究的结果 研究可能会导致合理的基因疗法的开发 治疗视网膜色素变性和其他视网膜变性。

DESCRIPTION (provided by applicant): Retinitis pigmentosa is a collection of inherited retinal degenerations affecting 50,000 to 100,000 individuals in the United States. Over the past decade, much progress has been made in identifying disease-causing genetic mutations. However, little is known about the mechanisms by which these mutations trigger photoreceptor cell death, making development of effective therapies difficult. The long-term objective of these studies is to identify molecular triggers of photoreceptor cell death. Specifically, these studies will test the hypothesis that genetic mutations that affect the signaling efficiency of rhodopsin cause retinal degeneration. The role of transducin signaling in retinal degenerative disease will be tested using signal-defective transgenic mice with a knock-out of the rod alpha-transducin gene. These mice will be used to test two proposed specific aims. Specific aim 1 will test the hypothesis that some rhodopsin mutations cause degeneration by the constitutive activation of transducin signaling, akin to retinal damage induced by continuous light exposure in rodents. Specific aim 2 will test the hypothesis that the opsin apoprotein, which may accumulate with defective rhodopsin regeneration, generates a signal that causes degeneration. To achieve these goals, rhodopsin mutant mice and opsin-producing transgenic mice will be crossed to transducin knock-out mice. Specific aim 3 will test the hypothesis that increase or decrease in rhodopsin density, which affects the efficiency of rhodopsin signaling, causes retinal degeneration. Levels of rhodopsin required to maintain normal retinal morphology, the time at which rhodopsin must be expressed to rescue degeneration, and how increased levels of wild type rhodopsin on a rhodopsin mutant background affects the severity of retinal degeneration will be defined. Specific aim 3 will be accomplished using transgenic mice with drug-inducible rhodopsin expression. The results of these studies could lead to the development of rational gene therapies for the treatment of RP and other retinal degenerations.