Novel TB Treatment Strategy - Optimization of Macrophage Responsiveness to IFNy

新型结核病治疗策略——优化巨噬细胞对 IFNy 的反应

基本信息

批准号：
9033071
负责人：
Igor Kramnik
金额：
$ 49.11万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
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：
2013-03-11 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9033071
关键词：
Acute Aerosols Anti-Bacterial Agents Antibiotic Resistance Bacteria Bacterial Infections Biological Assay Bone Marrow Boston Cell Line Cell Nucleus Cells Chemicals Chronic Clinical Clinical Research Collection Complement Dependence Development Disease Dose Drug Kinetics Drug Targeting Drug Tolerance Drug resistance Drug resistance in tuberculosis Elements Emerging Communicable Diseases FDA approved Granuloma HIV HIV/TB Host resistance Human Immunocompetent In Vitro Infection Infectious Diseases Research Inflammation Interferon Type II Interferons Intervention Lesion Libraries Listeria monocytogenes Lung Macrophage Activation Maintenance Methodology Modeling Mus Mutation Mycobacterium Infections Mycobacterium tuberculosis Necrosis Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Phase Play Predisposition Preventive Production Proteins Public Health Research Personnel Resistance Resistance to infection Role Safety Structure of parenchyma of lung Testing Therapeutic Therapeutic Agents Therapeutic Intervention Toxic effect Tuberculosis United States National Institutes of Health Universities Vaccines Validation Virulence Work abstracting base co-infection drug development improved improved outcome in vivo macrophage meetings mouse model mutant mycobacterial new therapeutic target novel pathogen prevent response restoration small molecule libraries transmission process treatment strategy tuberculosis treatment

项目摘要

Abstract The emergence and spread of disease caused by drug resistant forms of Mycobacterium tuberculosis (M.tb) represents a significant global threat, creating an urgent need for development of preventive and therapeutic strategies efficient against antibiotic-resistant M.tb. We propose a novel concept for developing drugs that cooperate with low doses of IFNg and selectively increase its beneficial effect on host resistance to infections. Essentiallity of the IFNγ pathway in resistance to a broad range of pathogens, including various mycobacterial species, has been convincingly demonstrated both in experimental mouse models and clinical studies. However, pathogens have evolved diverse mechanisms to suppress it. Therefore, therapeutic interventions aimed at restoration and maintanence of the IFNγ pathway may produce significant and long lasting impact on management of chronic infections. This approach will be especially useful in treatment of those chronic infections where the IFN pathway plays an essential role, but is compromised, either systemically (as in HIV and chronic TB infection) or locally (as within TB lesions). Our work will provide a basis for the development of a novel class of drugs targeting the host, not the pathogen, and therefore effective against antibiotic resistant bacteria. By helping control lung damage, these drugs will reduce the development and spread of drug resistant forms of tuberculosis.

抽象的结核分枝杆菌的耐药形式引起的疾病的出现和传播（M.TB）代表着重大的全球威胁，迫切需要开发预防和有效针对抗抗生素的M.TB的治疗策略我们提出了一个新颖的概念来发展用低剂量的IFNG教练并有选择地增加其对宿主的有益作用的药物对感染的抵抗力。 IFNγ途径的基本性对广泛的病原体的抗性包括各种分枝杆菌，在实验小鼠中都令人信服地证明了这两种物种模型和临床研究。然而，病原体已经发展出抑制它的多种机制。所以，旨在恢复和维持IFNγ途径的治疗干预措施可能会产生明显的以及对慢性感染管理的持久影响。这种方法将在治疗IFN途径起着至关重要但受到损害的慢性感染的治疗系统地（如艾滋病毒和慢性结核病感染）或局部（如结核病病变中）。我们的工作将提供开发针对宿主而不是病原体的新型药物的基础，因此有效针对抗生素抗性细菌。通过帮助控制肺部损伤，这些药物将减少发育和耐药形式的结核病。