An Inducible System for Gene Delivery

基因传递的诱导系统

• 批准号: 8816191
• 负责人: JEAN BENNETT
• 金额: $ 23.5万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-11 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8816191
• 关键词: Address; Affect; Age related macular degeneration; Bacteria; Basic Science; Binding; Biophysics; Blood Vessels; Cells; Choroidal Neovascularization; Clinical; Clinical Trials; Collaborations; Complex; Disease; Disease Progression; Elderly; Eye; Eye diseases; Funding; Gene Expression; Gene Expression Regulation; Goals; Hypoxia; In Vitro; Individual; Inherited; Injection of therapeutic agent; Lac Operon; Lactose; Lasers; Leber' s amaurosis; Measures; Medical; Mendelian disorder; Metabolism; Modeling; Molecular; Mus; Neurons; Operon; Patients; Play; Positioning Attribute; Property; Regulation; Research; Research Personnel; Research Proposals; Retina; Retinal; Retinal Diseases; Retinal Dystrophy; Retinal Neovascularization; Retinopathy of Prematurity; S cerevisiae SWI3 protein; Science; Solutions; System; Testing; Therapeutic; Transcript; Transcriptional Regulation; Transgenes; Translating; United States; Vascular Endothelial Growth Factors; Viral; Virus; Vision; Visual; base; combat; design; dosage; experience; gene delivery system; gene therapy; improved; in vitro Model; in vivo; mouse model; neovascular; next generation; nonhuman primate; promoter; public health relevance; therapeutic gene; three dimensional structure; tool; transgene expression

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.

描述：我们研究工作的最终目标是开发可诱导的开关，该开关可用于治疗眼睛的疾病，特别是与年龄相关的黄斑变性。这项研究建议是为了转化我们在转录调节方面的经验，并开发一种调节系统，以打击遗传和获得的眼睛的疾病。在这里，我们描述了一个基于调节LAC操纵子的开关调节转基因表达的新系统。该提案的具体目标是创建和定量评估可诱导的转基因输送调节系统以治疗眼部疾病。该提案是两位知名研究人员Drs之间的合作。刘易斯和贝内特。刘易斯实验室已经研究了诱导系统，尤其着重于调节细菌中乳糖代谢的操纵子。他们确定了与操作员和诱导剂绑定的阻遏物的三维结构[2]，已经建立了该诱导的开关的变构机制[3]，并进化了阻遏物及其操作员以创建一个最佳开关[4]。贝内特实验室（Bennett Lab）专注于理解视力的分子基础，并开发了治疗眼睛单基质疾病的理性方法。使用基因疗法，他们成功地恢复了患有Leber先天性症的患者的视力[5，6]。现在，我们处于一个独特的位置，可以结合我们的专业知识并翻译有关基因调节和基因疗法的发现，以开发下一代可诱导的开关来治疗各种视觉缺陷。这项研究的成功完成将 是调节治疗基因并治疗各种视网膜营养不良的诱导转换，包括与年龄相关的黄斑变性。