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Host responses to Mycobacterium infection in Zebrafish.

斑马鱼宿主对分枝杆菌感染的反应。

基本信息

批准号：
10153648
负责人：
LALITA RAMAKRISHNAN
金额：
$ 27万
依托单位：
UNIVERSITY OF CAMBRIDGE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10153648
关键词：
Antibiotic Resistance Apoptosis Bacteria Bacteriophages Biochemical Bioinformatics Cause of Death Cell Culture Techniques Cells Cessation of life Chemotaxis Data Development Dissection Drug Targeting ELF3 gene Epithelial Epithelial Cells Funding Gelatinase B Gene Expression Genetic Genetic Polymorphism Genetic Screening Genotype Genus Mycobacterium Goals Grant Granuloma Growth Hemolysin Human Immune response Infection Inflammation Institutes Integration Host Factors Kinetics Laboratories Libraries Life Cycle Stages MAPK8 gene Maintenance Maps Mediating Microscopic Modeling Molecular Mycobacterium Infections Mycobacterium marinum Mycobacterium tuberculosis NFKB Signaling Pathway Necrosis Optics Outcome Pathogenesis Pathway interactions Phagocytosis Pharmaceutical Preparations Pharmacology Phase Phenotype Predisposition Process Progress Reports Receptors, Tumor Necrosis Factor, Type II Research Role SP600125 Severities Signal Pathway Staphylococcus aureus Structure System TNF gene Techniques Testing Therapeutic Tuberculosis VDAC1 gene Virulence Virulent Zebrafish base forward genetics global health imaging capabilities leukotriene A4 hydrolase macrophage microscopic imaging migration mutant mycobacterial p38 Mitogen Activated Protein Kinase pathogen recruit response reverse genetics tool transcriptomics transmission process

项目摘要

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.

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。

项目成果

期刊论文数量（34）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The human proton pump inhibitors inhibit Mycobacterium tuberculosis rifampicin efflux and macrophage-induced rifampicin tolerance.

DOI：
10.1073/pnas.2215512120
发表时间：
2023-02-14
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Lake MA;Adams KN;Nie F;Fowler E;Verma AK;Dei S;Teodori E;Sherman DR;Edelstein PH;Spring DR;Troll M;Ramakrishnan L
通讯作者：
Ramakrishnan L

A zebrafish model for ocular tuberculosis.

DOI：
10.1371/journal.pone.0194982
发表时间：
2018
期刊：
PloS one
影响因子：
3.7
作者：
Takaki K;Ramakrishnan L;Basu S
通讯作者：
Basu S

Quantification of Feline immunodeficiency virus (FIVpco) in peripheral blood mononuclear cells, lymph nodes and plasma of naturally infected cougars.

自然感染美洲狮的外周血单核细胞、淋巴结和血浆中猫免疫缺陷病毒 (FIVpco) 的定量。

DOI：
10.1099/vir.0.81450-0
发表时间：
2006
期刊：
The Journal of general virology
影响因子：
0
作者：
Blake,DavidJ;Graham,Jon;Poss,Mary
通讯作者：
Poss,Mary

Phenolic Glycolipid Facilitates Mycobacterial Escape from Microbicidal Tissue-Resident Macrophages.

DOI：
10.1016/j.immuni.2017.08.003
发表时间：
2017-09-19
期刊：
Immunity
影响因子：
32.4
作者：
Cambier CJ;O'Leary SM;O'Sullivan MP;Keane J;Ramakrishnan L
通讯作者：
Ramakrishnan L

Gaucher disease protects against tuberculosis.

DOI：
10.1073/pnas.2217673120
发表时间：
2023-02-14
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Fan J;Hale VL;Lelieveld LT;Whitworth LJ;Busch-Nentwich EM;Troll M;Edelstein PH;Cox TM;Roca FJ;Aerts JMFG;Ramakrishnan L
通讯作者：
Ramakrishnan L