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Disease mechanism of Usher syndrome 2

亚瑟综合症2的发病机制

基本信息

批准号：
10733709
负责人：
Jun Yang
金额：
$ 46.91万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10733709
关键词：
Address Adhesions Affect Affinity Chromatography Age Animals Antibodies Area Biological Assay Biological Markers Blindness COL6A1 Catalytic Domain Cell physiology Clinical Co-Immunoprecipitations Cochlea Complex Cone Coupled Cultured Cells Cyclic AMP-Dependent Protein Kinases Defect Development Disease Electroretinography Extracellular Matrix Extracellular Matrix Proteins Functional disorder G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Gene Mutation Genes Immunoblot Analysis In Vitro Individual Inherited Investigation Knockout Mice Knowledge Label Light Mass Spectrum Analysis Mediating Membrane Membrane Proteins Membrane Transport Proteins Modeling Molecular Molecular Chaperones Multiprotein Complexes Mus Mutant Strains Mice Mutation Pathogenicity Pathway interactions Patients Persons Phosphorylation Photoreceptors Prevalence Protein Fragment Protein Inhibition Proteins Proteomics Recombinants Retina Retinal Defect Retinal Degeneration Retinitis Pigmentosa Role Signal Pathway Signal Transduction Structure Therapeutic Transfection USH2A gene Usher Syndrome Usher Syndrome Type 2 V1 Receptors Vertebrate Photoreceptors WHRN gene Work autosome deaf differential expression early onset effective therapy experimental study hearing impairment improved inherited retinal degeneration insight late-onset retinal degeneration molecular diagnostics mutant novel marker novel therapeutics phosphoproteomics postnatal prevent protein transport response therapeutic development therapeutic evaluation therapeutic target

项目摘要

Project Summary Retinitis pigmentosa (RP) is the predominant inherited retinal degenerative disease with a prevalence of 1 in 4,000 worldwide. RP combined with hearing loss is characterized as Usher syndrome (USH), which is the leading cause of inherited deaf-blindness. Currently, no cure is available for either RP or USH. USH2 is the most common USH clinical type. USH2A (usherin), ADGRV1 (adhesion G protein-coupled receptor V1), and WHRN (whirlin) have been identified as three USH2 causative genes. Among them, USH2A is the major causative gene for USH and autosomal recessive RP (arRP), and ADGRV1 is the second most frequent USH2 causative gene. In photoreceptors, usherin and ADGRV1 proteins interact with whirlin and form a multiprotein complex at the periciliary membrane between the inner and outer segment, but the functions of individual USH2 proteins as well as the entire USH2 complex have not been fully elucidated. This knowledge gap hinders the development of disease mechanism-based treatments. Since many patients carry USH2A mutations, the development and evaluation of therapeutics that target USH2A is an active area of investigation. However, the progress of these studies has been slowed down, because of the unknown early retinal molecular defects and late onset retinal degeneration in USH2 animal and/or in vitro retinal models. In our preliminary studies, we performed TMT-labeling quantitative proteomic and phosphoproteomic studies in USH2 mutant mouse retinas at postnatal day 30 long before retinal degeneration. We discovered alterations in photoreceptor outer segment membrane proteins, lipidated protein chaperones, BBSome and its cargos, extracellular matrix constituents, and protein kinase A signaling pathway. Affinity purification coupled with mass spectrometry experiments identified USH2 protein-interacting candidates that are enriched with proteins biologically associated with the early affected molecular and cellular processes in USH2 mutant retinas. We also found protein mislocalization and light response reduction in young USH2 mutant cones. Building on our extensive preliminary work, we propose to address the following specific aims in this application: 1) identify and investigate usherin- and ADGRV1-interacting proteins in the retina; 2) determine primary molecular defects in the retina of three different Ush2a and Adgrv1 mutant mice; and 3) uncover the molecular cause of early onset cone dysfunction in USH2 mutant retinas. If successful, our study will reveal the role of the USH2 complex in photoreceptors and provide insight into the pathogenic mechanisms underlying retinal degeneration caused by USH2 gene mutations. This study will also inform the development of mechanism-based new therapeutics for USH and arRP and discover valuable biomarkers that can be applied to therapeutic evaluation.

项目总结