A chemical approach to elucidating the structure-function relationships of chondr

阐明软骨结构与功能关系的化学方法

基本信息

批准号：
8220729
负责人：
Linda C Hsieh-Wilson
金额：
$ 39.33万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8220729
关键词：
Affect Affinity Chromatography Aging Anabolism Antibodies Axon Binding Proteins Biochemistry Biological Biological Process Biology Brain Carbohydrates Cell Communication Cells Cellular biology Charge Chemicals Chemistry Chondroitin Sulfate A Chondroitin Sulfate C Chondroitin Sulfates Code Communicable Diseases Crush Injury DNA Dendrites Development Disaccharides Disease Epitopes Generations Genes Genetic Global Change Grant Growth Imaging Device Injury Inorganic Sulfates Investigation Laboratories Learning Malignant Neoplasms Mammals Mass Spectrum Analysis Memory Molecular Molecular Structure Monoclonal Antibodies Myelin Natural regeneration Nerve Crush Nervous system structure Neurites Neurobiology Neurodegenerative Disorders Neuronal Injury Neurons Oligosaccharides Optic Nerve Organic Chemistry Pathway interactions Pattern Pharmacologic Substance Physiological Physiological Processes Play Polysaccharides Process Proteins RNA Regulation Research Retinal Retinal Ganglion Cells Role Source Spinal Cord Spinal cord injury Structure Structure-Activity Relationship Synapses Synthesis Chemistry Testing Therapeutic Intervention Unspecified or Sulfate Ion Sulfates Variant Viral Work axon growth axon guidance axon regeneration central nervous system injury chondroitin sulfate glycosaminoglycan design growth promoting activity in vivo inhibitor/antagonist insight marine organism mimetics neural circuit neuron development neuronal growth neurotrophic factor novel novel therapeutic intervention polymerization prevent public health relevance receptor repaired small molecule sulfation sulfotransferase tool

项目摘要

DESCRIPTION (provided by applicant): This project will focus on chondroitin sulfate (CS) glycosaminoglycans, a class of polysaccharides that play important roles in development, viral invasion, cancer, and spinal cord injury. CS polysaccharides display diverse sulfation patterns that are spatiotemporally regulated in vivo. However, efforts to identify functions for specific sulfation motifs have been hampered by the structural complexity of CS and a lack of tools. For instance, well-defined CS molecules cannot be purified from natural sources, and as a consequence, the field has been limited to working with heterogeneously sulfated mixtures of compounds. Genetic deletion of one of the sulfotransferase genes responsible for CS biosynthesis can propagate global changes throughout the carbohydrate chain, making it difficult to pinpoint the role of specific sulfation motifs. In this grant, we will combine the tools of organic chemistry and biology to overcome these challenges. We will exploit synthetic chemistry to assemble defined CS structures (both natural and non-natural) to obtain fundamentally new information about the structure- function relationships of CS. When combined with the power of biochemistry, genetics, cell biology, and neurobiology, these molecules will provide new insights into the physiological roles of carbohydrates in the nervous system and uncover novel mechanisms of neuronal growth and repair. As our project takes a distinctly chemical approach, this work may reveal novel proteins and pathways for therapeutic intervention and aid in the development of new pharmaceuticals to stimulate regeneration after injury, aging or disease. PUBLIC HEALTH RELEVANCE: This research seeks to understand how the structure of chondroitin sulfate glycosaminoglycans regulates fundamental biological processes, such as protein recognition and regulation, cell-cell communication, development, and regeneration after injury. Through the discovery of novel small molecules, proteins and pathways involved in these processes, this work may aid ultimately in the development of new therapeutic approaches to a broad range of disease states, such as cancer, infectious and neurodegenerative diseases.

描述（由申请人提供）：该项目将重点介绍硫酸软骨（CS）糖胺聚糖，这是一类在发育，病毒入侵，癌症和脊髓损伤中起重要作用的多糖。 CS多糖显示出多种硫酸化模式，这些硫酸化模式在体内受到时空调节。但是，CS的结构复杂性和缺乏工具的结构复杂性阻碍了识别特定硫酸基序的功能的努力。例如，定义明确的CS分子不能从天然来源纯化，因此，该领域仅限于使用化合物的异质硫酸化混合物。负责CS生物合成的硫代转移酶基因之一的遗传缺失可以在整个碳水化合物链中传播全局变化，因此很难确定特定硫酸化基序的作用。在这笔赠款中，我们将结合有机化学和生物学的工具，以克服这些挑战。我们将利用合成化学来组装定义的CS结构（自然和非天然），以获取有关CS结构功能关系的根本新信息。当结合生物化学，遗传学，细胞生物学和神经生物学的力量时，这些分子将提供有关碳水化合物在神经系统中生理作用的新见解，并发现神经元生长和修复的新型机制。由于我们的项目采用了明显的化学方法，这项工作可能揭示了治疗干预的新型蛋白质和途径，并有助于开发新药，以刺激受伤，衰老或疾病后的再生。公共卫生相关性：这项研究试图了解硫酸软骨素糖胺聚糖的结构如何调节基本生物学过程，例如蛋白质识别和调节，受伤后细胞细胞的交流，发育和再生。通过发现这些过程中涉及的新型小分子，蛋白质和途径，这项工作最终可能有助于开发针对广泛疾病状态的新治疗方法，例如癌症，传染性和神经退行性疾病。