Heparin Glycan Microarray for Screening

描述(由申请人提供)：拟议的研究计划将Solidus技术应用于微阵列、生物催化和筛选，并将Linhardt集团在肝素/硫酸肝素方面的专业知识应用于糖组学领域。糖组学是对糖链结构-功能关系的综合研究，是代谢组学的一个分支学科，是基因组学和蛋白质组学之外的下一步。肝素糖胺多聚糖(肝素和硫酸肝素)是结构最复杂的生物聚合物之一。这些多糖携带和存储重要的生物信息，在几乎所有涉及细胞间相互作用和交流的病理和病理生理过程中都是至关重要的。这一阶段STTR提案的具体目标和里程碑是：1.制备肝素多糖微阵列；2.用高度特异的肝素结合蛋白抗凝血酶III探测该微阵列；3.制备酶修饰的肝素多糖微阵列；4.用一系列肝素结合蛋白探测该微阵列以检测结合特异性；以及5.制备基于糖基转移酶延伸和酶修饰的肝素低聚糖受体的结构确定的糖微阵列，用于探测肝素结合蛋白。第一阶段将重点开发核心技术，以开发一种HepGly芯片，作为筛选与肝素结合蛋白相互作用的糖组学平台。HepGly微阵列的潜在应用包括开发下一代基于肝素的药物，评估与肝素/硫酸肝素与肝素结合蛋白相互作用拮抗的小分子药物，以及在诊断应用中快速筛选生物样本。将编制第二阶段提案，以开发这些商业应用。

DESCRIPTION (provided by applicant): The proposed research program applies Solidus technology in microarraying, biocatalysis, and screening and the Linhardt group's expertise in heparin/heparan sulfate to the field of glycomics. Glycomics, the comprehensive study of glycan structure-function relationship, is a sub-discipline of metabolomics and the next step beyond genomics and proteomics. Heparin glycosaminoglycans (heparin and heparan sulfate) are among the most structural complex biopolymers. These glycans carry and store significant biological information crucial in virtually all pathological and pathophysiological processes involving cell-cell interaction and communication. The specific aims and milestones of this Phase I STTR proposal are to: 1. prepare a heparin glycan microarray; 2. probe this microarray with the highly specific heparin-binding protein, antithrombin III; 3. prepare an enzyme-modified heparosan microarray; 4. probe this microarray with a collection of heparin-binding proteins to examine binding specificity; and 5. prepare a structurally defined glycan microarray based on the glycosyltransferase extension, and enzymatic modification of heparosan oligosaccharide acceptors for probing with heparin-binding proteins. Phase I will focus on developing the core technology required for developing a HepGly chip as a glycomics platform for screening interactions with heparin-binding proteins. Potential applications for a HepGly microarray include the development of the next generation of heparin-based drugs, the evaluation small molecule drugs that antagonize with heparin/heparan sulfate interaction with heparin-binding proteins and the rapid screening of biological samples in diagnostic applications. A phase II proposal will be prepared to develop these commercial applications.