Mechanisms Behind Retinal Photoreceptor Cells Outer Segment Biogenesis

视网膜感光细胞外节生物发生背后的机制

• 批准号: 9915928
• 负责人: Saravanan Kolandaivelu
• 金额: $ 37.5万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9915928
• 关键词: Address; Affect; Alleles; Amino Acids; Animal Model; Animals; Architecture; Atomic Force Microscopy; Biogenesis; Blindness; Canis familiaris; Cell Transplantation; Cellular biology; Complex; Cysteine; Defect; Development; Disease; Electron Microscopy; Exhibits; Functional disorder; GTP-Binding Proteins; Gene Transfer; Genes; Goals; Growth Factor; Guanosine Triphosphate Phosphohydrolases; Hand; Human; Inherited; Intervention; Knockout Mice; Knowledge; Label; Light; Link; Lipids; Maintenance; Membrane; Modification; Molecular; Morphogenesis; Morphology; Mutation; N-terminal; Neurons; Patients; Pharmacology; Phenotype; Photoreceptors; Phototransduction; Physiologic pulse; Physiological; Proteins; Publishing; Reagent; Research; Retina; Retinal Degeneration; Retinal Diseases; Retinal Photoreceptors; Retinitis Pigmentosa; Rhodopsin; Rod Outer Segments; Role; Severities; Signal Transduction; Spectrophotometry; Structure; Testing; Therapeutic; Time; Tissue Transplantation; Transducin; Transgenic Animals; Tyrosine; Vision; Work; base; clinically relevant; cone-rod degeneration; genome editing; mouse model; mutant; novel; palmitoylation; photoreceptor cell outer segment; programs; research study; trafficking; treatment strategy

PROJECT SUMMARY/ABSTRACT The long-term goal of our study is to decipher the mechanisms controlling the morphogenesis of the photoreceptor outer segment (OS), a cellular compartment vital for our vision. This proposal will specifically investigate the role of “Progressive Rod Cone Degeneration” (PRCD), in photoreceptor function and OS biogenesis. PRCD is exclusively present in photoreceptor OS disc membranes and associates with rhodopsin. The proposed studies are also clinically relevant as mutations in PRCD cause retinitis pigmentosa (RP) in humans and dogs. Our recent study showed that PRCD is post-translationally lipid modified by “palmitoylation” in a sole cysteine (Cys2), which is linked with RP in humans and dogs (Cys2Tyr). Despite the importance of PRCD in retinal function, the role for PRCD in photoreceptors is not known and is the main focus of this application. The first aim of this study will investigate the role of PRCD in photoreceptors using a novel PRCD-KO animal model generated by CRISP-Cas9 genome editing. The second aim will determine how the common patient mutation (C2Y) in PRCD leads to retinitis pigmentosa (RP) using multiple transgenic animal models. 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 PRCD mutations, and determine new potential therapeutic strategies for treatment such as gene transfer, tissue and cell transplantation, growth factor therapy, and pharmacological intervention.

项目概要/摘要 我们研究的长期目标是破译控制形态发生的机制 光感受器外节（OS），一个对我们的视觉至关重要的细胞区室。该提案将具体 研究“渐进性视杆锥体变性”(PRCD) 在感光器功能和 OS 中的作用 生物发生。 PRCD 专门存在于感光细胞 OS 盘膜中，并与 视紫红质。拟议的研究也具有临床相关性，因为 PRCD 突变会导致视网膜炎 人类和狗的色素性变性（RP）。我们最近的研究表明 PRCD 是翻译后脂质 通过唯一半胱氨酸 (Cys2) 中的“棕榈酰化”进行修饰，该半胱氨酸与人类和狗的 RP 相关 (Cys2Tyr)。尽管 PRCD 在视网膜功能中很重要，但 PRCD 在光感受器中的作用并不重要。 已知并且是该应用程序的主要焦点。本研究的第一个目的是调查 PRCD 的作用 使用通过 CRISP-Cas9 基因组编辑生成的新型 PRCD-KO 动物模型来研究光感受器。这 第二个目标是确定 PRCD 中常见的患者突变 (C2Y) 如何导致视网膜色素变性 （RP）使用多种转基因动物模型。我们提出的研究与视网膜疾病一致 NEI 计划“鉴定与遗传性和视网膜退行性疾病有关的基因” （包括 RP），确定 PRCD 突变的病理生理机制，并确定 新的潜在治疗策略，例如基因转移、组织和细胞移植， 生长因子治疗和药物干预。