Function of C8ORF37 in Photoreceptors

C8ORF37 在光感受器中的功能

基本信息

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
项目类别：
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

项目摘要

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.

项目概要视杆细胞和视锥细胞是感光细胞，分别负责弱光视觉和日光色觉。这视杆细胞和视锥细胞的外节（OS）是用于光转导的扩大的纤毛，包含许多紧密结合的纤毛。对齐的膜盘。在发育过程中，操作系统蛋白在内段合成，运输至连接纤毛的远端。这些操作系统蛋白随后有助于含有组织良好的膜盘的操作系统的形态发生。此过程中的缺陷与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与遗传性视网膜相关的基因来研究操作系统盘形态发生的机制退化。色素性视网膜炎（RP）是最常见的遗传性视网膜变性，患病率很高每 4,000 人中就有 1 人。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）是另一种遗传性视网膜变性的一种形式，患病率为四万分之一，影响视锥细胞或两者锥体和杆体同时进行。 C8ORF37 被确定为早发 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。 CRISPR/Cas9技术已培育出多个携带C8orf37突变的小鼠品系在我们的实验室。这些突变小鼠的表型特征发现 OS 膜紊乱椎间盘和操作系统形态发生过程中几种操作系统膜蛋白的减少。基于这些观察，本研究的中心假设是 C8ORF37 在光感受器 OS 盘中发挥作用通过参与一组 OS 膜蛋白的折叠、降解和/或运输来实现形态发生视杆细胞和视锥细胞。为了检验这一假设，将实现两个具体目标。在具体目标 1 中，主要 C8orf37 敲除小鼠中 OS 膜蛋白减少的原因将在以下两个方面进行研究杆和锥。将专门检查蛋白质折叠、运输和/或降解中的潜在缺陷。在具体目标 2 中，将通过研究 C8ORF37 功能的分子机制来解决革命性地改造 C8ORF37 的保守功能域并鉴定 C8ORF37 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，并可能有利于C8ORF37突变引起的RP和CRD的临床研究。