Function of C8ORF37 in Photoreceptors

C8ORF37 在光感受器中的功能

• 批准号: 9235479
• 负责人: Jun Yang
• 金额: $ 37.84万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9235479
• 关键词: Address; Affect; Animal Model; Biochemical; Biological Assay; Blindness; CRISPR/Cas technology; Carrier Proteins; Cell physiology; Cells; Cellular Structures; Cilia; Clinical Research; Color Visions; Complementary DNA; Cone; Cultured Cells; Data; Defect; Degradation Pathway; Dependovirus; Development; Disease; Distal; Electroretinography; Endoplasmic Reticulum; Endosomes; Exhibits; Genes; Goals; Impairment; In Situ; Inherited; Knock-out; Knockout Mice; Laboratories; Length; Ligation; Light; Maintenance; Mediating; Membrane; Membrane Proteins; Messenger RNA; Missense Mutation; Molecular; Morphogenesis; Mus; Mutant Strains Mice; Mutation; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Peripheral; Phenotype; Photoreceptors; Phototransduction; Prevalence; Process; Protein Family; Proteins; Research; Retina; Retinal; Retinal Cone; Retinal Degeneration; Retinal Pigments; Retinitis Pigmentosa; Rod Outer Segments; Role; Series; Technology; Tertiary Protein Structure; Testing; Vertebrate Photoreceptors; Vision; Visual Acuity; Yeasts; base; dynactin; early onset; gene therapy; guanylate cyclase 1; inherited retinal degeneration; insight; kinetosome; mutant; novel; peripherin; postnatal; protein E; protein degradation; protein folding; protein transport; response; retinal rods; screening; syntaxin; trafficking; yeast two hybrid system

Project Summary Rods and cones are photoreceptors responsible for dim light vision and day light color vision, respectively. The outer segment (OS) of rods and cones is an enlarged cilium for phototransduction containing many tightly- aligned membrane discs. During development, the OS proteins are synthesized in the inner segment and transported to the distal end of the connecting cilium. These OS proteins subsequently contribute to the morphogenesis of OSs containing well-organized membrane discs. Defects in this process are associated with various inherited retinal degenerative diseases. The long-term goal of our research is to understand the mechanism underlying OS disc morphogenesis through investigating genes associated with inherited retinal degenerations. Retinitis pigmentosa (RP) is the most common inherited retinal degeneration with a prevalence of 1 in 4,000 people. This disease affects rods and subsequently cones. Cone-rod dystrophy (CRD) is another form of inherited retinal degenerations with a prevalence of 1 in 40,000 people, affecting either cones or both cones and rods simultaneously. C8ORF37 was identified as a causative gene for early onset RP and CRD. This gene encodes a protein that does not belong to any protein families or possess any domains of known functions. Several mouse lines carrying C8orf37 mutations have been generated by CRISPR/Cas9 technology in our laboratory. Phenotypic characterization of these mutant mice found disorganization of OS membrane discs and reduction of several OS membrane proteins during OS morphogenesis. Based on these observations, the central hypothesis of this study is that C8ORF37 functions in photoreceptor OS disc morphogenesis by participating in folding, degradation and/or transport of a group of OS membrane proteins in both rods and cones. To test this hypothesis, two specific aims will be conducted. In specific aim 1, the primary cause underlying the decrease of OS membrane proteins in C8orf37 knockout mice will be investigated in both rods and cones. Potential defects in protein folding, transport and/or degradation will be specifically examined. In specific aim 2, the molecular mechanism underlying C8ORF37 function will be addressed by studying the revolutionarily conserved functional domain of C8ORF37 and identifying C8ORF37-interacting proteins. Completion of this study will provide new insights into OS disc morphogenesis in photoreceptors and may benefit clinical research on RP and CRD caused by C8ORF37 mutations.

项目摘要 视杆细胞和视锥细胞分别是负责弱光视觉和日光色觉的光感受器。的 视杆细胞和视锥细胞的外节（OS）是一个扩大的纤毛，用于光传导， 对齐的膜盘。在发育过程中，OS蛋白在内节合成， 运输到连接纤毛的远端。这些OS蛋白随后有助于 含有组织良好的膜盘的OS的形态发生。此过程中的缺陷与以下因素有关： 各种遗传性视网膜退行性疾病。我们研究的长期目标是了解 通过研究遗传性视网膜病变相关基因探讨OS椎间盘形态发生的机制 退化视网膜色素变性（RP）是最常见的遗传性视网膜变性， 4,000人中有1人死亡这种疾病影响视杆细胞，随后影响视锥细胞。锥杆营养不良（CRD）是另一种 一种遗传性视网膜变性，患病率为1/40，000，影响视锥细胞或两者 锥和杆同时。C8 ORF 37被鉴定为早发性RP和CRD的致病基因。 该基因编码的蛋白质不属于任何蛋白质家族，也不具有任何已知的结构域。 功能协调发展的已经通过CRISPR/Cas9技术产生了几种携带C8 orf 37突变的小鼠品系 在我们的实验室里。这些突变小鼠的表型特征发现OS膜的解体 在OS形态发生过程中，几种OS膜蛋白的减少。基于这些 本研究的中心假设是C8 ORF 37在光感受器OS盘中起作用， 通过参与一组OS膜蛋白的折叠、降解和/或转运， 视杆细胞和视锥细胞。为了检验这一假设，将进行两个具体的目标。在具体目标1中， C8 orf 37基因敲除小鼠OS膜蛋白减少的潜在原因将在两个实验中进行研究。 视杆细胞和视锥细胞。将专门检查蛋白质折叠、运输和/或降解的潜在缺陷。 在具体的目标2中，C8 ORF 37功能的分子机制将通过研究C8 ORF 37的功能来解决。 C8 ORF 37的革命性保守功能结构域和鉴定C8 ORF 37相互作用蛋白。 这项研究的完成将为光感受器中OS盘形态发生提供新的见解， 有益于C8 ORF 37突变引起RP和CRD的临床研究。