Development of an Immunostimulatory Small Molecule Library

免疫刺激小分子库的开发

• 批准号: 9302811
• 负责人: Catherine Leimkuhler Grimes
• 金额: $ 20.67万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9302811
• 关键词: Address; Alkynes; Alpha Cell; Anabolism; Asthma; Azides; Bacteria; Binding; Binding Proteins; Biochemistry; Biological; Biological Assay; Biomedical Engineering; Carbohydrates; Cell Wall; Cells; Chemicals; Chemistry; Chronic; Collection; Colon; Crohn' s disease; Development; Diagnosis; Disease; Electrochemistry; Enzymes; Event; Excision; Foundations; Glass; Glycosides; Goals; Human body; Immune System Diseases; Immune response; Immune signaling; Immune system; Immunologic Receptors; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Innate Immune Response; Innate Immune System; Investigation; Knowledge; Label; Laboratories; Lead; Libraries; Lung; Methods; Molecular; Molecular Biology; Monitor; Natural Immunity; Natural Products; Nature; Pathway interactions; Peptides; Peptidoglycan; Play; Polymers; Preparation; Production; Proteins; Research; Research Personnel; Research Project Grants; Research Proposals; Rheumatoid Arthritis; Role; Slide; Stomach; Structure; Surface; Techniques; Testing; Therapeutic; Work; base; body sense; cancer type; chemical synthesis; commensal microbes; design; effective therapy; immune activation; inhibitor/antagonist; member; novel; novel marker; novel therapeutics; professor; programs; response; screening; small molecule; small molecule libraries; sugar; therapy development; tool

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.

慢性炎症性疾病如哮喘、类风湿性关节炎和克罗恩病被认为是由不适当的免疫应答引起的。此外，各种类型的癌症，包括胃癌，结肠癌和肺癌，由于慢性炎症而出现。先天免疫系统与细菌的相互作用对这些疾病至关重要。已经表明，细菌细胞壁的片段激活先天免疫应答。细菌细胞壁是碳水化合物的聚合物。细菌细胞壁的活化片段的离散结构尚不清楚。为了更好地理解免疫疾病的分子基础，组装一组定义明确的碳水化合物探针至关重要。在这个子计划中，我们计划建立一个来源于细菌细胞壁的结构确定的碳水化合物库，以鉴定天然免疫应答的小分子探针。我们将使用两种不同的方法来产生碳水化合物文库：（1）化学合成和（2）细菌细胞壁生物合成的生物工程。然后，我们将在我们自己的实验室中筛选这些文库，以鉴定具有免疫刺激或免疫抑制活性的成员。此外，我们将打印这些文库作为微阵列，以便我们可以探测蛋白质相互作用。微阵列格式将使我们很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库来筛选与克罗恩病相关的新生物标志物。该项目采用独特的方法来解决主要问题 通过结合化学合成、细菌生物工程、分子生物学、生物化学和我们对先天免疫信号的知识，我们将解决先天免疫领域的问题。探针 在这个子项目中开发的新药物将用于开发治疗炎症性疾病的新疗法。