The primary Overall objective of the Resource for Integrated Glycotechnology is to develop novel, integrated technologies and multidisciplinary approaches to solve key problems in glycobiology. Protein-carbohydrate interactions play critical roles in numerous biological recognition events at the cell surface and extracellular matrix. The focus of our studies are proteoglycans (PGs), where extended, linear, charged glycan polymers are attached to cell surface or secreted proteins that contribute to cell-cell, cell-macromolecule, and cell-matrix interactions and influence numerous biological functions. Studies on protein-PG interactions are a prototype for more generalized studies on protein-carbohydrate interactions. Despite the critical importance of PGs in diverse biological processes, very little is known about the details of PG interactions with binding partners or their mechanisms of biological function. As a result, PG-protein interactions are a major technical frontier for contemporary biology. We will address the challenges of PG structures, interactions, and biological functions by leveraging advances in analytical, synthetic, structural, biochemical and biological tools. Technology Research and Development (TR&D) projects will be applied to the study of several Driving Biomedical Projects (DBPs) that will act as a test beds for the utility of the integrated approaches and provide feedback for new challenges that will spur further technology development. As the technologies mature they will be applied to a collection of Collaborative Projects and use in Analytical Services (C&S) that will also extend the utility of the technologies to a broader scientific community. Multiple strategies for Dissemination will increase awareness and access to the technology developments and our Training courses (D&T) will provide direct opportunities for researchers to learn the latest technology developments from Resource staff. The proposal aims to develop technologies (TR&Ds) to advance the goals of the DBPs through ligand identification and validation using PG fragment enrichment approaches, MS-based sequencing and composition analysis, and chemical glycan oligomer synthesis and array generation. Structures of PG-protein complexes will be determined using novel NMR methods and oxidative footprinting approaches and computational methods will predict and validate structure models. Biochemical targets will be generated in large quantities with isotopic labels and further modified to contain paramagnetic tags as needed to facilitate NMR studies. PG core proteins containing engineered glycan polymers will be generated using recombinant expression and cell systems harboring enhanced or mutant PG biosynthetic machinery. Mutant cell lines will also be used to characterize biological functions of PGs in appropriate biological contexts. The combined technology developments will advance our understanding of these critical glycan polymer structures and provide insights into their roles in human physiology and disease.
The interactions between glycosaminoglycans such as heparin, heparan sulfate, and chondroitin sulfate, and a variety of proteins involved in cellular signaling or cellular adhesion play important roles in human disease. These diseases include developmental abnormalities, cancer, coronary disease, a number of immune disorders and parasite invasion, malaria, for example. Understanding the molecular basis of specificity in these interactions is an essential component in the rational design of agents the can combat disease. The Resource for Integrated Glycotechnology develops methods that can provide this understanding.
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