Computational Genomics of Signal Transduction

项目总结 信号转导是一个普遍的生物过程，对所有生物体都是至关重要的。由于它们在疾病中的核心作用， 人类和细菌病原体的信号转导系统是药物设计的主要目标。我们的 长期目标是了解细胞如何检测、传输和适应信号。这个项目的主要关注点是 关于细菌趋化系统，这是理解信号基本原理的最好研究模型 在分子水平上的转导，也是许多致病细菌毒力的重要决定因素。 我们建议解决的主要悬而未决的问题是：(1)哪些小分子配体是 细菌识别，(2)这些信号如何从化学感受器传递到专用的激酶，以及 3)受体/激酶特异性的决定因素是什么。我们建议以我们之前的发现为基础，并 利用我们的工具开发，通过与几个实验项目合作来获取这些知识 实验室，并将这些知识作为预测模型来获取。这些模型将公开存储 数据库，如Pfam和我们自己的MIST(微生物信号转导)数据库。当前的雾化能力 将通过新的搜索和下载选项进行增强，并使用来自 人类微生物组计划和其他元基因组学数据集，导致资源可以更好地服务于 甚至是更大的科学界。最后，我们将把我们的进化分析扩展到关键的真核信号 转导途径，其中我们的目的是预测错义突变的后果 发育障碍和癌症。

PROJECT SUMMARY Signal transduction is a universal biological process vital to all organisms. Due to their central role in disease, signal transduction systems in humans and in bacterial pathogens are the primary targets of drug design. Our long-term goal is to understand how cells detect, transmit, and adapt to signals. The main focus of this project is on the bacterial chemotaxis system, which is the best studied model for understanding fundamentals of signal transduction at the molecular level and also an important determinant of virulence in many pathogenic bacteria. The main unanswered questions that we propose to address are: (1) which small molecule ligands are recognized by bacteria, (2) how these signals are transmitted from chemoreceptors to a dedicated kinase, and 3) what are the determinants of receptor/kinase specificity. We propose to build on our previous findings and capitalize on our tool development to obtain this knowledge in collaboration with several experimental laboratories and to capture this knowledge as predictive models. These models will be stored in public databases, such as Pfam and our own MiST (Microbial Signal Transduction) database. Current MiST capabilities will be enhanced with new search and download options and updated with a vast amount of sequences from the Human Microbiome Project and other metagenomics datasets, resulting in a resource that can better serve an even greater scientific community. Finally, we will extend our evolutionary analyses to the key eukaryotic signal transduction pathway, where we aim at predicting consequences of missense mutations in the context of developmental disorders and cancer.