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：
8506892
负责人：
Diane Joyce Ordway
金额：
$ 18.58万
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 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8506892
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）：由鸟分枝杆菌复合体、龟分枝杆菌、脓肿分枝杆菌和堪萨斯分枝杆菌引起的慢性肺病是美国新出现的严重公共卫生问题。由此类 NTM 引起的肺部疾病的发病率正在增加，最近的报告表明，在美国许多地区，NTM 肺部疾病的患病率超过了结核病。尽管采用各种多药方案进行长期治疗，但 NTM 引起的慢性肺部感染的治愈率仍然很低。人们对 NTM 感染的免疫发病机制的本质以及这些微生物如何克服宿主免疫并持续存在知之甚少；这是目前缺乏更有效和更有针对性的疗法开发的基础。开发 NTM 新疗法的两个限制，尤其是特别麻烦的脓肿分枝杆菌，是缺乏用于新药开发的先导化合物，以及缺乏经过验证的动物模型。然而，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，并且能够清除脓肿分枝杆菌的感染，从而使该模型不适合用于药物筛选。在这方面，我们需要进一步了解细菌清除和持久性的发病机制，并评估新的模型，在这些模型中，杆菌实际上可以生长到高水平，这样我们就可以利用这些模型来筛选新的疗法。我们在目标 1 中建议使用 GM-CSF-/-、MYD88-/-、TNFR-1-/-、C57BL/6NCrIBR 和 C3HeB/FeJ 和小鼠，以特征性支原体菌株标准化高气溶胶和静脉感染剂量。 avium 复合体、龟分枝杆菌、脓肿分枝杆菌和堪萨斯分枝杆菌，以评估后续发病机制并优化药物筛选模型。在目标 2 中，我们建议评估标准抗 NTM 化合物在这些模型中对抗 NTM 的功效。