Novel preclinical efficacy models against nontuberculosis mycobacteria

针对非结核分枝杆菌的新型临床前疗效模型

基本信息

批准号：
8604368
负责人：
Diane Joyce Ordway
金额：
$ 22.31万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-10 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8604368
关键词：
Acquired Immunodeficiency Syndrome Acute Address Aerosols Animal Model Animals Area Bacillus (bacterium)Bronchiectasis C3HeB/FeJ Mouse Cells Cessation of life Chronic Chronic lung disease Clinical Research Complex Contracts Cystic Fibrosis Data Depressed mood Development Diagnosis Disease Dose Equipment Evaluation Funding Gene Mutation Genes Genetic Genus Mycobacterium Granulocyte-Macrophage Colony-Stimulating Factor Heart Host Defense Human Immune Immunity Immunologic Deficiency Syndromes In Vitro Incidence Individual Infection Inflammatory Infiltrate Interferon Type II Interferons Interleukin-12 Intravenous Knock-out Knockout Mice Knowledge Lead Leptin Lung Lung diseases Mediating Medical Modeling Mouse Strains Mus Mutant Strains Mice Mycobacterium Infections Mycobacterium avium Complex Mycobacterium chelonae Mycobacterium kansasii Mycobacterium tuberculosis Myelogenous National Institute of Allergy and Infectious Disease Natural Immunity Nature Necrosis Neutropenia Organism Pathogenesis Patients Pharmaceutical Preparations Preclinical Drug Evaluation Prevalence Public Health Regimen Reporting Signal Transduction Skin Soft Tissue Infections Source T-Lymphocyte TNF gene Testing Toll-Like Receptor 2 Toll-like receptors Tuberculosis Tumor Necrosis Factor Receptor United States Water Water Pollution Woman Work base dectin 1 drug development high risk human TNFRSF1A protein human data in vivo neutrophil novel preclinical efficacy programs public health relevance pulmonary granuloma soft tissue tumor necrosis factor alpha receptor

项目摘要

DESCRIPTION (provided by applicant): Chronic lung disease due to Mycobacterium avium complex, Mycobacterium chelonae, Mycobacterium abscessus, and Mycobacterium kansasii are an emerging and serious public health problem in the United States. The incidence of pulmonary disease caused by such NTM is increasing and recent reports suggest that in many areas of the U.S., the prevalence of NTM pulmonary disease exceeds that of tuberculosis. The cure rate for chronic lung infections due to NTM are low despite prolonged treatment with various multi-drug regimens. Little is known about the nature of the immunopathogenesis of NTM infections and how these organisms overcome host immunity and persist; this underlies the current lack of development of more efficacious and targeted therapies. The two limitations to developing new therapies for NTM, especially the particularly troublesome M. abscessus, are the lack of lead compounds for new drug development, and the lack of a validated animal model. Our recent preliminary data using infection of GKO-/- mice however showed that these mice still possessed robust innate immunity and were able to clear an infection with M. abscessus bacilli making this model unsuitable for drug screening. In this regard, we need to further understand the pathogenesis involved in bacterial clearance and persistence and evaluate new models in which the class of bacilli can actually grow to high levels so we can use these models to screen for new therapies. We propose in aim 1 to use GM-CSF-/-, MYD88-/-, TNFR-1-/-, C57BL/6NCrIBR and C3HeB/FeJ and mice to standardize a high aerosol and intravenous infection dose with characterized strains of M. avium complex, M. chelonae, M. abscessus, and M. kansasii to evaluate the subsequent pathogenesis and optimize the model for drug screening. In Aim 2 we propose to evaluate the efficacy of standard anti-NTM compounds against NTMs in these models.

描述（由申请人提供）：由于分枝杆菌群，分枝杆菌，枝状脓肿，脓肿分枝杆菌和Kansasii造成的慢性肺疾病是美国的新兴而严重的公共卫生问题。这种NTM引起的肺疾病的发生率正在增加，最近的报道表明，在美国许多地区，NTM肺疾病的患病率超过了结核病。尽管多种多药方案进行了长时间的治疗，但由于NTM引起的慢性肺部感染的治愈率较低。关于NTM感染的免疫发病的性质以及这些生物如何克服宿主的免疫和持续存在的性质知之甚少。这是目前缺乏更有效和有针对性疗法的发展。为NTM开发新疗法的两个局限性，尤其是特别麻烦的超麻子。但是，我们最近使用GKO - / - 小鼠感染的初步数据表明，这些小鼠仍然具有强大的先天免疫力，并且能够清除脓肿支原体杆菌的感染，从而使该模型不适合药物筛查。在这方面，我们需要进一步了解细菌清除和持久性涉及的发病机理，并评估新模型，其中细菌类实际上可以生长到高水平，以便我们可以使用这些模型来筛查新疗法。 We propose in aim 1 to use GM-CSF-/-, MYD88-/-, TNFR-1-/-, C57BL/6NCrIBR and C3HeB/FeJ and mice to standardize a high aerosol and intravenous infection dose with characterized strains of M. avium complex, M. chelonae, M. abscessus, and M. kansasii to evaluate the subsequent pathogenesis and optimize the model for drug筛选。在AIM 2中，我们建议在这些模型中评估标准抗NTM化合物对NTM的功效。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mycobacterium avium Infection in a C3HeB/FeJ Mouse Model

C3HeB/FeJ 小鼠模型中的鸟分枝杆菌感染

DOI：
10.3389/fmicb.2019.00693
发表时间：
2019
期刊：
Frontiers in Microbiology
影响因子：
5.2
作者：
Verma, Deepshikha;Stapleton, Megan;Gadwa, Jake;Vongtongsalee, Kridakorn;Schenkel, Alan R.;Chan, Edward D.;Ordway, Diane
通讯作者：
Ordway, Diane