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：
8511008
负责人：
Igor Kramnik
金额：
$ 22.31万
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：
2013-03-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8511008
关键词：
2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole 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 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 Outcome 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 base drug development improved in vivo macrophage meetings mouse model mutant mycobacterial novel pathogen prevent public health relevance response restoration small molecule libraries transmission process treatment strategy tuberculosis treatment

项目摘要

DESCRIPTION (provided by applicant): The emergence and spread of disease caused by drug resistant forms of Mycobacterium tuberculosis (Mtb) represents a significant global threat, creating an urgent need for development of preventive and therapeutic strategies efficient against antibiotic-resistant Mtb. We propose a novel concept for developing drugs that cooperate with low doses of IFN-? and selectively increase its beneficial effect on host resistance to infections. Essentiality of the IFN-? 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 maintenance of the IFN-? 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.

描述（由申请人提供）：由结核分枝杆菌（MTB）耐药形式引起的疾病的出现和传播代表了一个重大的全球威胁，迫切需要开发针对抗抗生素的MTB的预防和治疗策略。我们提出了一个新颖的概念，用于开发与低剂量IFN-合作的药物？并有选择地提高其对宿主对感染的抗性的有益作用。 IFN-的重要性？在实验小鼠的模型和临床研究中，人们都令人信服地证明了对广泛病原体的抗性途径，包括各种分枝杆菌。然而，病原体已经发展出抑制它的多种机制。因此，旨在恢复和维护IFN-的治疗干预措施？途径可能会对慢性感染管理产生重大持久的影响。这种方法将在治疗那些ifn-的慢性感染中特别有用。途径在系统上（如HIV和慢性结核病感染）或局部（如结核病病变中），途径扮演着重要的作用，但受到损害。我们的工作将为靶向宿主而不是病原体的新型药物的发展提供基础，因此为抗生素耐药细菌有效。通过帮助控制肺部损伤，这些药物将减少结核病的耐药形式的发展和扩散。