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

Functional mechanisms underlying Dystroglycan-dependent and independent roles of protein O-mannosylation in the nervous system

蛋白质 O-甘露糖基化在神经系统中依赖和独立作用的功能机制

基本信息

批准号：
10207792
负责人：
VLADISLAV M PANIN
金额：
$ 31.06万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
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：
2017-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10207792
关键词：
Affect Afferent Neurons Animals Area Axon Biochemical Bioinformatics Biological Biological Process Biology Biomedical Research Cells Clinical Research Communication Complex Data Defect Development Developmental Biology Diagnostic Disease Drosophila genus Dystroglycan Embryo Genes Genetic Genetic Diseases Glycobiology Glycoproteins Human Imaging Techniques In Vitro Investigation Light Mediating Mediator of activation protein Membrane Proteins Methods Modeling Modernization Modification Molecular Molecular Target Muscle Muscle Contraction Muscular Dystrophies Nervous system structure Neurobiology Organism Outcome Pathogenicity Pathway interactions Pattern Phenotype Physiology Play Polysaccharides Post-Translational Protein Processing Posture Protein Tyrosine Phosphatase Proteins Regulation Research Role Severities Structure Testing Therapeutic base dystroglycanopathy genetic approach glycoproteomics glycosylation human disease in vivo innovation multidisciplinary muscle physiology mutant neuromuscular novel novel therapeutics protein function receptor receptor function

项目摘要

The main objective of this project is to elucidate functional mechanisms underlying regulation of the nervous system by protein O-mannosylation (POM). POM is an essential type of O-glycosylation that has a profound effect on the development and physiology in a broad range of animals, from Drosophila to humans. Although the spectrum of biological functions affected by POM is wide, so far the only well-studied target of POM is Dystroglycan (Dg). Defects in POM modifications of Dg result in severe muscular dystrophies called dystroglycanopathies. Pathomechanisms associated with POM defects are complex and remain poorly understood, particularly in the nervous system. Recent studies suggested that POM modification affects functions of many proteins, which contributes to pathogenic mechanisms of dystroglycanopathies. However, functions of POM on proteins besides Dg are largely unknown. The complexity of glycosylation and limitations of in vivo approaches create significant challenges for studying POM in mammalian organisms. Here we propose a multidisciplinary project that uses advantages of Drosophila model, including powerful arsenal of genetic approaches, simplified glycosylation and experimental amenability of POM and Dg mutants, to elucidate molecular and cellular mechanisms of Dg- dependent and Dg-independent functions of POM, with the focus on the nervous system and neuromuscular development and physiology. Our preliminary studies suggested that Receptor Protein Tyrosine Phosphatases (RPTPs) are functionally important POM targets and revealed that POM regulates coordinated muscle contractions by affecting communication between sensory neurons and the CNS. We will capitalize on these results while focusing on three specific aims: (1) To analyze the role of POM in regulation of sensory neurons and coordinated muscle contractions. Using live imaging techniques combined with genetic and neurobiological approaches, we will comprehensively investigate the role of POM in communication between sensory neurons, CNS cells and muscles. (2) To investigate the effect of POM on RPTP function. Using in vivo and in vitro approaches, we will investigate how POM affects functions RPTPs at molecular, cellular, and organismal levels. (3) To reveal new molecular targets of POM and elucidate their function in the nervous system. We will use glycoproteomic approaches to identify proteins with POM modifications. We will analyze functions of POM on novel targets in vivo, focusing on proteins that function in the nervous system. We anticipate that this project will establish new paradigms of POM-mediated regulation of the nervous system and will elucidate new evolutionarily conserved, Dg- dependent and independent mechanisms of POM functions, which will shed light on pathomechanisms of human diseases associated with POM abnormalities.