Host responses to Mycobacterium infection in Zebrafish.

我们使用斑马鱼模型来详细描述结核病中的宿主-病原体界面，我们的发现 导致了对炎症、巨噬细胞和肉芽肿在 感染在这样做的过程中，我们也更好地了解了基本的主机过程 特别是涉及巨噬细胞和炎症的那些。在下一阶段的拨款中，我们将继续 描述新发现的改变分枝杆菌感染的宿主因子的作用。其中一些 在上一个供资期内已经确定但尚未充分确定， 我们现在正在继续的斑马鱼突变体筛选，使用全面测序的斑马鱼， 桑格研究所创建的突变体库，并提供给我们。全面 转录组学也将在桑格研究所进行，并得到生物信息学的全面支持， 我们的重点是改变易感性的突变体的表型特征。的进步 显微成像能力，不断发生在我们的实验室，和使用 药理学方法的额外途径解剖和药物鉴定，我们希望有一个 在下一个阶段加快发现的步伐。 相关性（参见说明）： 结核病是全世界死亡的主要原因，也是一个日益严重的全球健康问题。结核病已经 由于多种因素的结合，包括抗生素耐药性的发展，难以根除。我们 研究提出，确定战略和分子，可以指导发展的新类别， 治疗结核病的宿主靶向药物。

We have used the zebrafish model to detail the host-pathogen interface in tuberculosis, and our discoveries have led to a more nuanced understanding of the role of inflammation, macrophages and granulomas in infection. In so doing, we have also achieved a better understanding of fundamental host processes particularly those involving macrophages and inflammation. In this next phase of the grant, we will continue to characterize the role of newly-identified host factors that alter mycobacterial infection. Some of these were already identified but not fully characterized in the last funding period, and others will be identified in the zebrafish mutant screen that we are continuing now, using the comprehensive sequenced zebrafish mutant library that has been created by the Sanger Institute and made available to us. Comprehensive transcriptomics will also be carried out for us at the Sanger Institute with full bioinformatics support, leaving us to focus on the phenotypic characterization of the mutants with altered susceptibility. With advances in microscopic imaging capability that are continuously occurring in our laboratory, and the use of pharmacological approaches for additional pathway dissection and drug identification, we hope to have an accelerated pace of discovery during this next phase. RELEVANCE (See instnJctions): Tuberculosis is a leading cause of death worldwide and a growing global health concern. TB has been difficult to eradicate due to a combination of factors, including the development of antibiotic resistance. Our research proposes to identify strategies and molecules that can direct development of new classes of host-targeting drugs to treat TB.