An Inducible System for Gene Delivery

产品说明：我们研究工作的最终目标是开发一种可用于治疗眼部疾病的诱导开关，特别是年龄相关性黄斑变性。这项研究计划是将我们在转录调控方面的经验转化为发展一个调控系统，用于对抗遗传性和获得性眼病。在这里，我们描述了一个新的系统来调节转基因表达的基础上的开关，调节乳糖操纵子。本发明的具体目标是建立和定量评估用于治疗眼部疾病的诱导型转基因递送调节系统。这项建议是两个既定的研究者，刘易斯和班尼特博士之间的合作。刘易斯实验室研究了诱导系统，特别关注调节细菌乳糖代谢的操纵子。他们确定了阻遏物的三维结构，与操纵子和诱导子结合[2]，建立了这种诱导型开关的变构机制[3]，并进化了阻遏物及其操纵子以创建最佳开关[4]。班尼特实验室致力于了解视觉的分子基础，并开发治疗眼部单基因疾病的合理方法。使用基因疗法，他们成功地恢复了患有Leber先天性黑蒙的患者的视力[5，6]。我们现在处于一个独特的位置，联合收割机结合我们的专业知识，并翻译我们已经发现的基因调控和基因治疗，以开发下一代的诱导开关治疗各种视觉缺陷。这项研究的成功完成将 作为一个诱导开关，用于调节治疗基因和治疗各种视网膜营养不良，包括年龄相关性黄斑变性。

DESCRIPTION: The ultimate goal of our research efforts is to develop an inducible switch that could be used to treat diseases of the eye, specifically age-related macular degeneration. This research proposal is to translate our experience with regard to transcriptional regulation and develop a regulatory system for combating both inherited and acquired diseases of the eye. Here, we describe a new system to regulate transgene expression based upon the switch that regulates the lac operon. The specific goal of this proposal is to create and quantitatively evaluate an inducible transgene delivery regulatory system to for treating eye diseases. This proposal is a collaboration between two established investigators, Drs. Lewis and Bennett. The Lewis lab has studied inducible systems, focusing particularly on the operon that regulates lactose metabolism in bacteria. They determined the three-dimensional structure of the repressor, bound to operator and inducers [2], have established the allosteric mechanism of this inducible switch [3], and have evolved the repressor and its operator to create an optimal switch[4]. The Bennett lab has focused on understanding the molecular basis of vision and developing rational approaches for treating monogenic diseases of the eye. Using gene therapy, they successfully restored vision in patients suffering from Leber's congenital amaurosis [5, 6]. We are now in a unique position to combine our expertise and translate what we have discovered about gene regulation and gene therapy to develop the next generation of inducible switches for treating a variety of visual deficits. The successful completion of this research will be an inducible switch for regulating therapeutic genes and treating a variety of retinal dystrophies including age-related macular degeneration.