Genetic Analyses of Heparan Sulfate Function in Cell-Cell Interactions

硫酸乙酰肝素在细胞-细胞相互作用中功能的遗传分析

基本信息

批准号：
8598913
负责人：
Hannes Erich Buelow
金额：
$ 31.73万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8598913
关键词：
Address Anabolism Anatomy Animals Biochemical Biochemistry Biological Assay Caenorhabditis elegans Cell Communication Cells Characteristics Communicable Diseases Complex Development Environment Extracellular Matrix Extracellular Space Genes Genetic Glycosaminoglycans Growth Factor Heparan Sulfate Proteoglycan Heparitin Sulfate Human Imagery Intervention Life Malignant - descriptor Malignant Neoplasms Modeling Modification Molecular Movement Nematoda Neoplasm Metastasis Nervous system structure Neuroglia Neurons Organism Pathology Pathway interactions Phenotype Physiological Physiological Processes Play Polymers Process Proteins RNA Interference Reading Role Signal Transduction Site Structure Structure-Activity Relationship Subcellular structure Time Transgenic Organisms Vertebrates cancer cell cell motility cofactor developmental disease extracellular genetic analysis human disease in vivo insight intercellular communication migration mutant nervous system development neurodevelopment novel pathogen public health relevance research study sugar sulfation syndecan tool tumor

项目摘要

DESCRIPTION (provided by applicant): Cell migrations are a characteristic of multicellular life, both during development and malignant or, pathological states. A molecularly complex extracellular landscape plays a crucial role in directing migrating cells. One of the most complex structures in the extracellular space is heparan sulfate proteoglycans (HSPGs) that have been shown to be essential for cell-cell signaling. Here we propose to study the function of heparan sulfate proteoglycans in cellular migration using stereotypic cell migrations in the small nematode C. elegans which require HSPGs for function. To this end we are using an integrated approach that combines biochemical studies with genetic approaches to directly correlate protein and sugar structure of HSPGs with their function during cell migration. Our project will compare distinct cell migrations that we know already employ distinct molecular mechanisms, including distinct HS sugar structures. Lastly, we will define the global HS landscape that migrating cells encounter. To this end we will use a novel tool we have developed that allows the direct visualization of HS motifs in living animals. Our studies will allow correlating HS structure with cellular and subcellular localization. In summary, the proposed studies will provide insight into the cell-specific and sugar-dependent mechanisms that migrating cells use to interpret the extracellular space. Understanding fundamental aspects of cell-specific interactions of migrating cells may ultimately allow the cell-specific intervention during diseased states.

描述（由申请人提供）：细胞迁移是多细胞生命的一个特征，无论是在发育过程中还是在恶性或病理状态下。分子复杂的细胞外景观在引导细胞迁移中起着至关重要的作用。细胞外空间最复杂的结构之一是硫酸乙酰肝素蛋白聚糖 (HSPG)，它已被证明对于细胞间信号传导至关重要。在这里，我们建议利用需要 HSPG 发挥功能的小型线虫秀丽隐杆线虫中的刻板细胞迁移来研究硫酸乙酰肝素蛋白多糖在细胞迁移中的功能。为此，我们正在使用一种综合方法，将生化研究与遗传方法相结合，将 HSPG 的蛋白质和糖结构与其在细胞迁移过程中的功能直接关联起来。我们的项目将比较不同的细胞迁移，我们知道这些细胞迁移已经采用了不同的分子机制，包括不同的 HS 糖结构。最后，我们将定义迁移细胞遇到的全球 HS 景观。为此，我们将使用我们开发的一种新颖工具，可以直接可视化活体动物中的 HS 基序。我们的研究将允许 HS 结构与细胞和亚细胞定位相关联。总之，拟议的研究将提供深入了解迁移细胞用来解释细胞外空间的细胞特异性和糖依赖性机制。了解迁移细胞的细胞特异性相互作用的基本方面可能最终允许在患病状态下进行细胞特异性干预。