Biosynthesis and trafficking of phosphodiesterase in the retinal photoreceptors

视网膜感光细胞中磷酸二酯酶的生物合成和运输

• 批准号: 10376198
• 负责人: Visvanathan Ramamurthy
• 金额: $ 37.63万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10376198
• 关键词: Address; Affect; Anabolism; Animal Model; Animals; Aryl Hydrocarbon Receptor; Biochemical; Blindness; Catalytic Domain; Cell Transplantation; Childhood; Client; Clinical; Color blindness; Complex; Cone; Defect; Disease; Electrophysiology (science); Enzymes; Excision; Exhibits; Gene Transfer; Genes; Goals; Growth Factor; Hand; Heat-Shock Proteins 90; Human; In Vitro; Inherited; Intervention; Knock-in; Knowledge; Lead; Light; Link; Lipids; Measurement; Mediating; Membrane; Modeling; Modification; Molecular; Molecular Chaperones; Monitor; Morphology; Mus; Mutation; Neurons; Pathway interactions; Patients; Pharmacology; Photoreceptors; Phototransduction; Positioning Attribute; Post-Translational Protein Processing; Protein Biosynthesis; Regulation; Research; Retina; Retinal Degeneration; Retinal Diseases; Retinal Photoreceptors; Retinitis Pigmentosa; Rod; Role; Signal Transduction; Stimulus; Testing; Therapeutic; Time; Tissue Transplantation; Vision; Visual; achromatopsia; base; design; farnesylation; geranylgeranylation; in vivo; inhibitor; isoprenylation; mouse model; mutant; novel; novel therapeutics; phosphodiesterase 6; phosphoric diester hydrolase; prevent; programs; receptor; repaired; response; retinal rods; trafficking; treatment strategy

PROJECT SUMMARY/ABSTRACT The long term goals of our research are to study the role of post-translational protein modifications and their role in phototransduction protein synthesis and maturation. The purpose of this proposal is to investigate the importance of the isoprenylation of phosphodiesterase-6 (PDE6) in retinal photoreceptor neurons. PDE6 is an enzyme that is essential for vision, and its absence or mutations in humans lead to retinitis pigmentosa (RP) and color blindness. Interestingly, changes in Aryl hydrocarbon receptor protein-like-1 (AIPL1), a co- chaperone for PDE6 leads to more severe childhood blindness. Despite the clear link to several blinding diseases, our knowledge on assembly and maturation of this essential enzyme in photoreceptor neurons is not known. Our study will specifically focus on the interplay between AIPL1, HSP90, and lipid modification in PDE6 assembly, maturation, and trafficking to the photoreceptor outer segments. We will also study the importance of differential isoprenylation in mediating light-dependent signaling in the photoreceptor cells. We will use a combination of unique animal models, in vivo electrophysiological measurements, ex vivo retinal culture models and in vitro biochemical analyses to comprehensively address this question. Our proposed studies are aligned with the Retinal Diseases Program of the NEI to “Identify the genes involved in both inherited and retinal degenerative diseases (including RP), determine the pathophysiological mechanisms underlying these mutations, and determine new potential therapeutic strategies for treatment such as gene transfer, tissue and cell transplantation, growth factor therapy, and pharmacological intervention.” Our proposed studies have clinical implications, such as therapy for mutations in PDE6 and AIPL1 that lead to blindness in humans.

项目摘要/摘要 我们研究的长期目标是研究翻译后蛋白质修饰及其的作用 在光转导蛋白合成和成熟中的作用。该提议的目的是调查 视网膜光感受器神经元中磷酸二酯酶6（PDE6）的异on基化的重要性。 PDE6是 一种对视觉至关重要的酶，其在人类中的缺失或突变导致色素性视网膜炎 （RP）和色盲。有趣的是，芳基烃受体蛋白样-1（AIPL1）的变化， PDE6的伴侣会导致更严重的儿童失明。尽管与几个盲人有明确的联系 疾病，我们在光感受器神经元中这种基本酶的组装和成熟的知识是 不知道。我们的研究将特别关注AIPL1，HSP90和脂质修饰之间的相互作用 PDE6组装，成熟和贩运光感受器外部段。我们还将研究 差异异丙基化在介导光感受器细胞中的光依赖性信号传导中的重要性。 我们将使用独特的动物模型的组合，体内电生理测量，离体 视网膜培养模型和体外生化分析可全面解决这个问题。 我们提出的研究与NEI的视网膜疾病计划一致，以“识别基因 涉及遗传和视网膜退行性疾病（包括RP），确定 这些突变基础的病理生理机制，并确定新的潜在疗法 治疗策略，例如基因转移，组织和细胞移植，生长因子治疗以及 药理学干预。”我们提出的研究具有临床意义，例如治疗 PDE6和AIPL1的突变导致人类失明。