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

Mapping glycan-dependent neurexin interactomes

映射聚糖依赖性神经毒素相互作用组

基本信息

批准号：
10675699
负责人：
Mia L Huang
金额：
$ 18.1万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10675699
关键词：
Architecture Binding Binding Proteins Biochemistry Biology Brain Calcium Catalogs Cell Adhesion Molecules Cell surface Cells Chemicals Cognition Disorders Communication Complex Comprehension Core Protein Data Defect Development Disease Engineering Enzyme-Linked Immunosorbent Assay Evaluation Event Exhibits Gilles de la Tourette syndrome Glycoconjugates Glycosaminoglycans Goals Heterogeneity Hippocampus In Vitro Knowledge Lead Ligands Maintenance Maps Mass Spectrum Analysis Mediating Modification Mus Neurons Outcome Pattern Phase Polysaccharides Process Protein Glycosylation Protein Isoforms Protein Tyrosine Phosphatase Proteoglycan Proteomics Research Resolution Reverse engineering Schizophrenia Structure Structure-Activity Relationship Sulfate Synapses Techniques Technology Transact Transfection Work design empowerment genetic approach genetic manipulation glycosylation human interactome innovation intercellular connection nervous system disorder neural pleiotrophin presynaptic neurons protein protein interaction protein structure synaptic function targeted treatment technology platform tool

项目摘要

PROJECT SUMMARY Neurexin is an important cell adhesion molecule on pre-synaptic neurons that mediates important binding events to form synapses, the most fundamental unit of neuronal communication. Alterations in neurexin structure underlie many cognitive and neurological diseases. Our limited understanding of neurexin structure hampers our ability to develop targeted therapies to alleviate these disorders. Recent discoveries have found that neurexin is a glycoconjugate decorated with diverse glycosaminoglycan structures. These findings are exciting and prompt the requirement for a comprehensive and glycan-dependent understanding of neurexin structure-binding relationships. However, such studies are challenging, given the diversity and heterogeneity of glycosaminoglycans. Using an innovative proteoglycan editing platform rooted in chemical biology, we will fabricate defined and replete neurexin ectodomains and refine binding relationships with known binding partners (evaluation phase, Aim 1). Subsequently, we will apply these molecules to live primary neurons and display them in a de novo fashion on cell surfaces, such that we can use proximity tagging to capture their corresponding interactomes (discovery phase, Aim 2). These sophisticated materials will serve as important tools to define and evaluate neurexin ligands, and the overall outcome of this application will be a catalogue of neurexin interactomes defined by their glycosylation states.

项目总结 Neuresin是突触前神经元上的一种重要的细胞黏附分子，介导重要的结合事件形成突触，这是神经元交流的最基本单位。神经脲素结构的改变这是许多认知和神经疾病的基础。我们对Neuresin结构的有限理解阻碍了我们的有能力开发有针对性的治疗方法来缓解这些疾病。最近的发现发现，纽瑞新是一种一种装饰有不同糖胺多聚糖结构的糖偶联物。这些发现是令人兴奋和迅速的对Neuresin结构结合的全面和依赖于糖的理解的要求两性关系。然而，考虑到生物多样性和异质性，这类研究具有挑战性。糖胺聚糖。使用植根于化学生物学的创新蛋白多糖编辑平台，我们将构建已定义和丰富的Neuresin胞外结构域，并改进与已知结合伙伴的结合关系 (评价阶段，目标1)。随后，我们将把这些分子应用于活的初级神经元并展示它们以一种从头开始的方式在细胞表面上，以便我们可以使用邻近标记来捕捉它们对应的互动(发现阶段，目标2)。这些复杂的材料将作为重要工具来定义和评估neuresin配体，这一应用的总体结果将是neuresin的目录由糖基化状态定义的相互作用。