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The differential behavior of Prph2/Rom1 in rods and cone contributes to Prph2-associated disease heterogeneity

Prph2/Rom1 在视杆细胞和视锥细胞中的差异行为导致与 Prph2 相关的疾病异质性

基本信息

批准号：
10513307
负责人：
Larissa Ikelle
金额：
$ 4.06万
依托单位：
UNIVERSITY OF HOUSTON
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：
2021-09-28 至 2026-09-27
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10513307
关键词：
Address Affect Affinity Animal Model Attention Backcrossings Behavior Binding Biochemical Bypass Cells Clinical Co-Immunoprecipitations Complex Cone Data Development Disease Disease model Electron Microscopy Etiology Exhibits Future Goals Golgi Apparatus Health Homo Homologous Gene Imaging Techniques Impairment In Vitro Inherited Investigation Knock-out Knowledge Leucine Zippers Macular degeneration Maintenance Membrane Microdomains Membrane Proteins Methods Modeling Modification Molecular Conformation Morphogenesis Mutation Nature Neural Retina Outcome Outcome Study Pathogenicity Pathology Pathway interactions Patients Pattern Phenotype Photoreceptors Process Proteins Psammomys Rattus Research Resolution Retina Retinal Diseases Retinitis Pigmentosa Rod Rod Outer Segments Rodent Model Role Sand Rats Severity of illness Silicon Dioxide Structure Therapeutic Three-dimensional analysis Vertebrate Photoreceptors cell type conditional knockout disease heterogeneity disease phenotype effective therapy in vivo in vivo Model innovation interest macular dystrophy microscopic imaging mutant overexpression pattern dystrophies peripherin syntaxin therapeutically effective trafficking

项目摘要

PROJECT SUMMARY Mutations in Peripherin 2 (PRPH2) account for a significant portion of inherited retinal diseases (IRD). Delineating the role of PRPH2 in photoreceptor morphogenesis and rim formation is vital to understand how mutations in a single protein could contribute to such diverse group of pathologies, ranging from retinitis pigmentosa (RP) to pattern dystrophy (PD) and macular degeneration (MD). Even patients with intrafamilial mutations can exhibit a notable degree of phenotypic variability, attesting to the complex nature in which PRPH2 functions. My objective in this application is to advance our current knowledge of the role of PRPH2 in outer segment (OS) formation in order to have a better understanding of disease pathogeneses and for future development of effective therapeutic strategies. Over the years, our lab has developed an extensive toolbox of in vitro and in vivo mutant models, and are currently exploring innovative imaging techniques to further our understanding of the role of Prph2 in OS landscape. Thus far, it has been determined that the association between Prph2 and its homologue, Rod OS Protein 1 (Rom1), contributes significantly to the phenotypic variability observed in patients and that lowering Rom1 levels could shift a sever Prph2-assocaited PD phenotype to milder RP. Furthermore, it is know that the proper function of Prph2 at the disc rim is contingent upon proper complex assembly of Prph2-oligomers and Prph2/Rom1-complexes. The central focus of this investigation is to understand how Prph2 and Rom1 function differently in rods and cones with particular interest in Prph2 homo- and Prph2/Rom1 hetero-complex formation/trafficking, and the effects of Prph2 mutations on these processes. We propose two aims to address these goals: Aim 1 will assess the role of Rom1 in cones and the mechanism by which it modulates Prph2-disease phenotypes. By eliminating or overexpressing Rom1 in Prph2-disease models, we will conduct careful biochemical, structural, and functional analyses to assess phenotypic differences, as they pertain to complex assembly and OS trafficking. Aim 2 will investigate the role of interacting partners in the differential behavior of Prph2 in rods vs cones. In order to properly traffic and function in the OS, Prph2 forms membrane microdomains to organize and house a network of proteins that are necessary/specific for the formation of the closed rims in rods and open lamellae/rims in cones. In this aim, we will identify critical Prph2 binding partners and determine how these interactions differ between rods and cones. The outcomes of these studies will elucidate the specific function of Prph2 and Rom1 in rods and cones, determine how modulating Rom1 affects disease phenotypes, and will further our understanding of the role of Prph2 in the closed rim structure in rods and the open rim structures in cones. Given the lack of effective treatments for Prph2-associated diseases, these studies are essential and bring attention to the role of Rom1 as a common disease modulator for future development of effective therapeutic strategies.

项目总结