Development of an Immunostimulatory Small Molecule Library

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Chronic inflammatory diseases such as asthma, rheumatoid arthritis, and Crohn's disease are thought to arise from an inappropriate immune response. In addition, a variety of types of cancers including gastric, colon and lung arise due to chronic inflammation. The innate immune system's interaction with bacteria is critical to these diseases. It has been shown that fragments of bacterial cell wall activate an innate immune response. The bacterial cell wall is a polymer of carbohydrates. The discrete structures of the activating fragments of bacterial cell wah are not known. In order to better understand the molecular basis of immunological diseases it is critical that a collection of well-defined carbohydrate probes be assembled. In this subproject, we propose to establish a library of structural defined carbohydrates derived from bacterial cell wall to identify small molecule probes ofthe innate immune response. We will use two different methods to produce the carbohydrate libraries: (1) chemical synthesis and (2) bioengineering of bacterial cell wall biosynthesis. We will then screen these libraries in our own laboratory to identify members that have immuno-stimulatory or immuno-inhibitory activity. In addition, we will print these libraries as microarrays so that we may probe for protein interactions. The microarray format will make it easy for us to distribute our libraries to other investigators. In addition, we will use the bacterial cell wall libraries to screen for novel biomarkers associated with Crohn's disease. This project takes a unique approach to addressing major problems in the field of innate immunity through the combination of chemical synthesis, bacterial bioengineering, molecular biology, biochemistry and our knowledge of innate immune signaling. The probes that are developed in this subproject will be useful in the development of new therapeutics for the treatment of inflammatory disorders.