权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Disease mechanisms of cone opsin mutants and treatment strategies

视锥细胞突变体的致病机制及治疗策略

基本信息

批准号：
10400427
负责人：
Wen-Tao Deng
金额：
$ 38.13万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10400427
关键词：
Affect Biochemical Biogenesis CRISPR/Cas technology Categories Cell Death Color Color Visions Complementary DNA Cone Cone dystrophy Defect Dimerization Disease Dominant-Negative Mutation Dorsal Endoplasmic Reticulum Foundations Functional disorder Future Genes Goals Human In Vitro Knock-in Knock-in Mouse Knock-out Knockout Mice Knowledge Lead Light Link Maintenance Mediating Membrane Messenger RNA Modeling Molecular Mus Mutation Myopia Natural regeneration Opsin Outcome Pathogenicity Patients Phenotype Photoreceptors Phototransduction Physiological Play Point Mutation Population Property Proteins Research Resistance Resolution Retina Retinal Cone Retinal Diseases Retinal Pigments Retinitis Pigmentosa Rhodopsin Rod Role Signal Transduction Small Interfering RNA Solid Structure Supplementation Technology Testing Therapeutic Transgenic Mice Vertebrate Photoreceptors Vision Disorders Visual Work adeno-associated viral vector blue cone monochromacy dimer effective therapy functional loss gene replacement therapy gene therapy improved in vivo in vivo Model innovation macula mutant retinal rods spatial vision success therapy design treatment strategy

项目摘要

ABSTRACT L- and M- cones constitute about 95% of the total cone population, primarily concentrated in the macula, they are responsible for our daylight, central high resolution, and color vision. Mutations in the L-opsin and M-opsin genes are associated with a variety of visual defects including red-green color vision deficiency, blue cone monochromacy (BCM), X-linked cone dystrophy/dysfunction, and high myopia with abnormal cone function. Currently studies on disease mechanisms of cone opsin mutations have been mostly carried out in vitro, therefore the impact of these mutations on cone structure and their physiological consequences are not well understood. Recent studies suggest that rhodopsin dimerization plays a central role in signal transduction and that defects in dimerization are one molecular mechanism associated with some forms of rhodopsin-related autosomal dominant retinitis pigmentosa. Relative to rhodopsin, studies of cone opsin organization in outer segment membranes have been lagging primarily because cones are less abundant than rods thus hampering a detailed structural analysis. Our goals are to elucidate the molecular mechanisms underlying cone opsin mutations in vivo to develop effective treatment approaches, and to understand the organization of cone opsins in outer segment membranes and pathophysiology associated with cone opsin dimerization disruption. Our prior studies have demonstrated that AAV-mediated expression of human L-opsin and M-opsin promotes regrowth of cone outer segments and rescues M-cone function in the treated M-opsin knockout (Opn1mw-/- ) mouse, a model for BCM. One critical observation from our work is that cone opsins are required for outer segment formation, but not for cone viability. These results lead us to propose the use of the Opn1mw-/- mice as an in vivo model to investigate disease mechanisms associated with cone opsin mutants via our well- developed AAV-mediated cone targeting approach (Aim 1). Our preliminary results using this approach indicate that the cone opsin C203R mutation, responsible for more than half of the BCM population, displays a dominant-negative phenotype. We have generated a knock-in mouse line carrying this mutation and will test gene therapy options (Aim 2). The success of these strategies can be employed to treat other cone opsin mutations displaying dominant-negative phenotypes. We will also employ a combination of AAV technology, biochemical approaches, and transgenic mice to define domains involved in cone opsin dimerization and characterize the pathophysiology associated with dimerization disruption (Aim 3). Completing these goals will provide us a solid foundation for developing effective strategies to treat different categories of retinal disease caused by cone opsin mutations. This study will also improve our knowledge of the roles cone opsins play in outer segment disc membrane formation and maintenance.

摘要