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：
10426737
负责人：
Mia L Huang
金额：
$ 31.06万
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/10426737
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 (Brain)In Vitro Knowledge Lead Ligands Maintenance Maps Mass Spectrum Analysis Mediating Modification Mus Neurons Outcome Pattern Phase Plant Roots 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 base design genetic approach genetic manipulation glycosylation human interactome innovation intercellular connection nervous system disorder pleiotrophin presynaptic neurons protein protein interaction protein structure relating to nervous system synaptic function targeted treatment 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.

项目摘要神经毒素是介导重要结合事件的突触前神经元上重要的细胞粘附分子形成突触，这是神经元交流的最基本单位。神经结构的改变基于许多认知和神经系统疾病。我们对神经结构的有限理解阻碍了我们的能够开发有针对性疗法以减轻这些疾病的能力。最近的发现发现神经毒素是一种糖缀合物，装饰有多种糖胺聚糖结构。这些发现令人兴奋且迅速对神经结构结合的全面和聚糖依赖性理解的要求关系。但是，鉴于多样性和异质性，此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聚糖编辑平台，我们将捏造定义和填充神经毒素的外生域，并与已知结合伙伴的完善结合关系（评估阶段，目标1）。随后，我们将将这些分子应用于原发性神经元并显示以细胞表面的从头形式以从头开始，以便我们可以使用接近标签来捕获其相应的相互作用体（发现阶段，目标2）。这些复杂的材料将作为定义和评估神经毒素配体，该应用的总体结果将是神经毒素的目录由其糖基化态定义的相互作用体。