Development of an Immunostimulatory Small Molecule Library

慢性炎症性疾病，如哮喘、类风湿关节炎和克罗恩病被认为是由不适当的免疫反应引起的。此外，包括胃癌、结肠癌和肺癌在内的多种癌症都是由慢性炎症引起的。先天免疫系统与细菌的相互作用对这些疾病至关重要。研究表明，细菌细胞壁碎片可激活先天免疫反应。细菌的细胞壁是碳水化合物的聚合物。细菌细胞wah的激活片段的离散结构尚不清楚。为了更好地了解免疫疾病的分子基础，组装一组定义良好的碳水化合物探针是至关重要的。在这个子项目中，我们建议建立一个来自细菌细胞壁的结构定义碳水化合物库，以识别先天免疫反应的小分子探针。我们将使用两种不同的方法来生产碳水化合物库：(1)化学合成和(2)细菌细胞壁生物合成的生物工程。然后，我们将在自己的实验室筛选这些文库，以确定具有免疫刺激或免疫抑制活性的成员。此外，我们将这些文库打印为微阵列，以便我们可以探测蛋白质相互作用。微阵列格式将使我们更容易将我们的文库分发给其他研究人员。此外，我们将使用细菌细胞壁文库筛选与克罗恩病相关的新型生物标志物。这个项目采用了一种独特的方法来解决主要问题

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.