Genetic Mechanisms of Retinal Degenerative Disease

描述（由申请人提供）：视网膜色素变性是一个集合， 遗传性视网膜变性影响50，000至100，000人， 美国的在过去十年中，在确定 致病基因突变然而，人们对此知之甚少。 这些突变触发感光细胞死亡的机制， 有效的治疗方法很难。这些长期目标 研究的目的是确定感光细胞死亡的分子触发因素。 具体来说，这些研究将检验基因突变 影响视紫红质的信号传导效率导致视网膜变性。 转导蛋白信号在视网膜变性疾病中的作用将被测试 使用信号缺陷的转基因小鼠， α-转导素基因。这些小鼠将被用于测试两个拟议的具体 目标。具体目标1将测试假设，一些视紫红质突变， 通过转导素信号传导的组成性激活引起变性， 啮齿类动物因持续光照而导致的视网膜损伤。具体目标 2将测试的假设，视蛋白脱辅基蛋白，这可能会积累与 有缺陷的视紫红质再生，产生导致变性的信号。 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， 将小鼠与转导蛋白敲除小鼠杂交。具体目标3将测试 假设增加或减少视紫红质密度，这影响了 视紫红质信号传导的效率，导致视网膜变性。水平 视紫红质维持正常视网膜形态所需的时间， 视紫红质必须表达以挽救退化，以及如何增加视紫红质的水平。 在视紫红质突变体背景上的野生型视紫红质影响 将定义视网膜变性。具体目标3将使用 具有药物诱导的视紫红质表达的转基因小鼠。的结果予以 研究可能会导致合理的基因疗法的发展， 治疗RP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.