Heparan sulfate in neurophysiology and neurological disorders

硫酸乙酰肝素在神经生理学和神经系统疾病中的作用

基本信息

批准号：
9105755
负责人：
YU YAMAGUCHI
金额：
$ 42.57万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-15 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9105755
关键词：
Address Autistic Disorder Autopsy Behavioral Binding Biochemical Biological Biological Process Brain Brain region Carbohydrate Chemistry Cell Adhesion Molecules Cell Surface Receptors Cell surface Cells Cellular biology Centers for Disease Control and Prevention (U.S.)Child Cognitive Complex Core Protein Country Development Diagnosis Disease Employee Strikes Epitopes Event Excitatory Synapse Experimental Genetics Extracellular Matrix Family Functional disorder Genes Genetic Glutamate Receptor Glutamates Glycosaminoglycans Growth Health Heparan Sulfate Proteoglycan Heparitin Sulfate High Prevalence Human Human Genetics Impairment Inorganic Sulfates Knock-out Knockout Mice Lead Ligands Link Mediating Medical Genetics Mental disorders Minor Molecular Mus Mutant Strains Mice Mutation Neurons Nonverbal Communication Pathogenesis Pathway interactions Pattern Phenotype Physiological Play Polysaccharides Positioning Attribute Property Proteoglycan Proteomics Public Health Reciprocal Social Interaction Reporting Research Risk Role Series Signal Transduction Social Conditions Specificity Structure Susceptibility Gene Symptoms Synapses Synaptic Transmission Testing Unspecified or Sulfate Ion Sulfates autism spectrum disorder base brain tissue editorial epimerization experience in vivo insight interest morphogens mouse model nervous system disorder neurodevelopment neuroligin 1 neurophysiology novel therapeutics postnatal repetitive behavior research study response social sugar sulfation synaptic function

项目摘要

DESCRIPTION (provided by applicant): Heparan sulfate (HS) is a highly sulfated polysaccharide that occurs on the cell surface and in the extracellular matrix as proteoglycans. HS interacts with a variety of soluble ligands, such as growth factors and morphogens, as well as cell surface receptors, and thereby plays critical roles in diverse cell surface signaling event. HS is the most structurally complex glycosaminoglycan containing variable numbers of sulfate groups at the N-, 2-O-, 3-O-, and 6- O-positions of the sugar chain. "HS fine structure" originating from such complex patterns of sulfation often constitutes critical determinants of the binding specificity to ligands and, as a result, the biological function of HS. Although it has lon been known that HS is concentrated in synapses, the role of HS in neurophysiology and its potential relevance to neurological and mental disorders have not been satisfactorily elucidated. To address these issues, we created conditional knockout mice in which HS expression is ablated specifically in postnatal neurons. These mutant mice displayed striking recapitulation of numerous autism-related behavioral phenotypes, and HS-deficient neurons showed impaired glutamatergic synaptic transmission due to reduced recruitment of glutamate receptors to synapses. More recently, we found that HS binds neuroligins, a family of synaptic adhesion molecules that have strong implications in autism, and regulates their multimerization. In this project, we will use mouse genetics, neuronal cell biology, and state-of-the-art carbohydrate chemistry to determine the role of HS and its fine structure in neurophysiology and the pathogenesis of autism. Specific aims are: 1. Determine the biochemical property of synaptic HS and characterize its changes in response to different social conditions and in autistic brains. 2. Determine the mechanism by which HS regulates neuroligin-dependent synapse assembly and maturation. 3. Examine the physiological relevance of the neuroligin-HS interaction by mouse genetics and proteomic experiments.

描述（由申请人提供）：硫酸乙酰肝素 (HS) 是一种高度硫酸化的多糖，存在于细胞表面和细胞外基质中，因为 HS 与多种可溶性配体（例如生长因子和形态发生素）相互作用。 HS 是细胞表面受体，并在多种细胞表面信号转导事件中发挥关键作用，因此是结构最复杂的糖胺聚糖，含有不同数量的糖胺聚糖。糖链的 N-、2-O-、3-O- 和 6-O- 位上的硫酸根源自这种复杂的硫酸化模式，通常构成与配体结合特异性的关键决定因素。因此，HS 的生物学功能虽然人们早就知道 HS 集中在突触中，但 HS 在神经生理学中的作用及其与神经和精神疾病的潜在相关性尚未得到证实。为了解决这些问题，我们创建了条件敲除小鼠，其中 HS 表达在出生后神经元中被特异性消除，这些突变小鼠表现出许多与自闭症相关的行为表型，并且 HS 缺陷的神经元表现出谷氨酸能突触传递受损。减少谷氨酸受体向突触的募集最近，我们发现 HS 与神经连接蛋白（neuroligins）结合，神经连接蛋白是突触粘附分子家族，在在这个项目中，我们将利用小鼠遗传学、神经细胞生物学和最先进的碳水化合物化学来确定 HS 及其精细结构在神经生理学和自闭症发病机制中的作用。目标是： 1. 确定突触 HS 的生化特性，并表征其对不同社会条件和自闭症大脑的反应的变化。 2. 确定 HS 调节神经胶质素依赖性突触的机制。 3.通过小鼠遗传学和蛋白质组学实验检查neuroligin-HS相互作用的生理相关性。