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: 10132339
• 负责人: Visvanathan Ramamurthy
• 金额: $ 38.08万
• 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/10132339
• 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/antagonist; 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.

项目概要/摘要 我们研究的长期目标是研究翻译后蛋白质修饰的作用及其作用 该提案的目的是研究光转导蛋白合成和成熟中的作用。 磷酸二酯酶 6 (PDE6) 的异戊二烯化在视网膜感光神经元中的重要性是。 一种对视力至关重要的酶，其在人类中的缺失或突变会导致色素性视网膜炎 (RP) 和色盲。 PDE6 的伴侣会导致更严重的儿童失明，尽管它与多种致盲现象有明确的联系。 疾病，我们对感光神经元中这种必需酶的组装和成熟的了解是 我们的研究将特别关注 AIPL1、HSP90 和脂质修饰之间的相互作用。 我们还将研究 PDE6 的组装、成熟和运输至光感受器外节。 差异异戊二烯化在介导感光细胞中的光依赖性信号传导中的重要性。 我们将结合使用独特的动物模型、体内电生理测量、离体 视网膜培养模型和体外生化分析可以全面解决这个问题。 我们提出的研究与 NEI 的视网膜疾病计划一致，旨在“识别基因 涉及遗传性和视网膜退行性疾病（包括 RP），确定 这些突变背后的病理生理机制，并确定新的潜在治疗方法 治疗策略，例如基因转移、组织和细胞移植、生长因子治疗和 药物干预。”我们提出的研究具有临床意义，例如治疗 PDE6 和 AIPL1 突变会导致人类失明。