Drosophila screens to isolate genes that modulate outer-segment membrane disc bio

果蝇筛选分离调节外节膜盘生物的基因

• 批准号: 8621455
• 负责人: Andrew Zelhof
• 金额: $ 22.88万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8621455
• 关键词: Affect; Affinity; Antibodies; Biochemical; Biogenesis; Biological Assay; Biology; Cell Extracts; Cell physiology; Data; Defect; Detection; Development; Disease; Drosophila genus; Excision; Generations; Genes; Genetic; Genetic Screening; Genomics; Heterozygote; Housing; Human; In Vitro; Inherited; Invertebrates; Knock-out; Knowledge; Light; Maintenance; Membrane; Modeling; Molecular; Morphogenesis; Mus; Mutagenesis; Mutate; Mutation; Opsin; Organelles; Outcome; Pathway interactions; Phenotype; Photoreceptors; Phototransduction; Procedures; Process; Proteins; Proteomics; RNA Interference; Retinal Cone; Retinal Degeneration; Retinal Diseases; Retinitis Pigmentosa; Role; Spectrophotometry; Structure; Therapeutic Intervention; Time; Transgenic Organisms; Vertebrate Photoreceptors; Vertebrates; Vesicle; base; cofactor; dosage; in vivo; insight; knock-down; membrane biogenesis; mutant; photoreceptor disc; prominin; protein complex; public health relevance; retinal rods; tissue culture; trafficking

Project Summary/Abstract: Retinitis Pigmentosa (RP) defines a broad group of inherited retinal disorders characterized by the degeneration of rod and cone photoreceptors. A salient feature of photoreceptors is the presence of an elaborate membrane structure that houses opsin and associated phototransduction machinery required for light detection, the membrane discs of the outer-segment (OS) in vertebrates and the rhabdomeres of invertebrates. With respect to RP, many of the diseased loci are critical for the creation and maintenance of OS, the light gathering organelle. Thus our challenge is that if any advancement is going to be made toward effective therapeutic intervention with regards to mutations that perturb OS biogenesis a coherent understanding of the normal cellular mechanisms for biogenesis is essential. To date the molecular and cellular mechanisms required for OS formation are undefined and competing models exist. This proposal will focus on the biology of Prominin to further our knowledge of outer-segment membrane disc morphogenesis. Prominin localizes to the newly formed nascent discs. Directed murine knock-out of Prominin1, analyses of several inherited human retinopathies, and Drosophila prominin mutants have all demonstrated an essential role for Prominin in generating and maintaining the integrity of the photoreceptor light gathering organelles. In this proposal we combine the technological advances of proteomics and genetic in vivo capacity of Drosophila to explore numerous unanswered facets of Prominin biology required for disc membrane morphogenesis and photoreceptor integrity. The discovery of these pathways will contribute to our understanding of the cellular functions required for OS membrane disc morphogenesis, the molecular mechanisms of Prominin induced retinal degeneration, and reveal potential avenues for therapeutic intervention.

项目摘要/摘要： 色素性视网膜炎 (RP) 定义了一大类遗传性视网膜疾病，其特征是 视杆细胞和视锥细胞感光细胞变性。光感受器的一个显着特征是存在 复杂的膜结构，容纳视蛋白和相关的光转导机制所需的 光检测、脊椎动物外节 (OS) 的膜盘和 无脊椎动物。就 RP 而言，许多患病基因座对于 RP 的产生和维持至关重要。 OS，光收集细胞器。因此，我们面临的挑战是，如果要在这方面取得任何进展， 针对扰乱操作系统生物合成的突变进行有效的治疗干预 了解生物发生的正常细胞机制至关重要。迄今为止，分子和 操作系统形成所需的细胞机制尚未定义，并且存在竞争模型。该提案将 重点关注 Prominin 的生物学，以加深我们对外节膜盘形态发生的了解。 Prominin 定位于新形成的新生椎间盘。定向小鼠 Prominin1 敲除，分析 几种遗传性人类视网膜病和果蝇 prominin 突变体都显示出一种重要的 Prominin 在产生和维持光感受器集光细胞器完整性中的作用。在 该提案我们结合了蛋白质组学的技术进步和果蝇体内的遗传能力 探索椎间盘膜形态发生所需的 Prominin 生物学的许多未解答的方面，以及 光感受器完整性。这些途径的发现将有助于我们对细胞的理解 OS膜盘形态发生所需的功能，Prominin诱导的分子机制 视网膜变性，并揭示治疗干预的潜在途径。