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

• 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
• 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

 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（由申请方提供）：硫酸乙酰肝素（HS）是一种高度硫酸化的多糖，作为蛋白聚糖存在于细胞表面和细胞外基质中。HS与多种可溶性配体（如生长因子和形态发生素）以及细胞表面受体相互作用，从而在多种细胞表面信号传导事件中起关键作用。HS是结构最复杂的糖胺聚糖，在糖链的N-、2-O-、3-O-和6-O-位置含有不同数量的硫酸酯基团。源自这种复杂的硫酸化模式的“HS精细结构”通常构成与配体的结合特异性的关键决定因素，并因此构成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障碍的潜在相关性尚未得到令人满意的阐明。为了解决这些问题，我们创建了条件性基因敲除小鼠，其中HS表达在出生后的神经元中特异性地被消融。这些突变小鼠表现出惊人的重演许多自闭症相关的行为表型，和HS缺陷的神经元表现出受损的谷氨酸能突触传递由于减少招募谷氨酸受体的突触。最近，我们发现HS结合神经配素，一个在自闭症中具有强烈影响的突触粘附分子家族，并调节其多聚化。在这个项目中，我们将使用小鼠遗传学，神经元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。具体目标是：1。确定突触HS的生化特性，并描述其在不同社会条件下和自闭症患者大脑中的变化。2.确定HS调节神经连接素依赖性突触组装和成熟的机制。3.通过小鼠遗传学和蛋白质组学实验检查神经连接素-HS相互作用的生理相关性。