Boosting Innate Immunity Through HIF to Treat Antibiotic-Resistant Infections

通过 HIF 增强先天免疫力来治疗抗生素耐药性感染

基本信息

批准号：
8076598
负责人：
RANDALL Scott JOHNSON
金额：
$ 103.61万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-05 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8076598
关键词：
Abscess Address Agonist Anti-Bacterial Agents Anti-Infective Agents Antibiotic Resistance Antibiotic Therapy Antibiotics Apoptosis Apoptotic Bacteria Bacterial Infections Basic Science Biotechnology Cell Death Cells Cellular biology Chlamydophila pneumoniae Chromatin Clinical Trials Collaborations Companions Cutaneous Cytoplasmic Granules Data Development Development Plans Discipline Drug Design Drug Kinetics Elements Epithelial Epithelium Gene Expression Regulation Gene Targeting Generations Genes Genetic Goals Gold Healed Host Defense Human Hypoxia Immune Immunogenetics Immunotherapeutic agent In Vitro Industry Infection Infectious Skin Diseases Inflammatory Investigational New Drug Application Knockout Mice Knowledge Laboratories Lead Leukocytes Lipopolysaccharides Lung Manuscripts Mediating Medicine Modeling Molecular Mus Myelogenous Myeloid Cells NIH Program Announcements National Institute of Allergy and Infectious Disease Natural Immunity Necrosis Nitric Oxide Pathway interactions Pattern Peptide Hydrolases Phagocytes Pharmaceutical Preparations Pharmacologic Substance Pharmacology Pneumonia Positioning Attribute Preparation Procollagen-Proline Dioxygenase Production Program Development Pseudomonas Infections Pseudomonas aeruginosa Publishing Puncture procedure Research Research Personnel Resistance Resolution Role Safety Skin Staphylococcal Infections Staphylococcus aureus Systemic Therapy TNF gene Therapeutic Toll-like receptors Topical agent Toxic effect Toxin Transcriptional Regulation Translational Research Vancomycin Work Wound Infection antimicrobial antimicrobial peptide bacterial resistance bactericide cytokine drug resistant bacteria extracellular healing hypoxia inducible factor 1 in vivo in vivo Model industry partner inhibitor/antagonist innate immune function innovation keratinocyte killings macrophage mast cell methicillin resistant Staphylococcus aureus microbial microbicide mouse model neutrophil novel overexpression pathogen pre-clinical product development promoter response subcutaneous superinfection synergism tool transcription factor treatment strategy treatment trial wound

项目摘要

DESCRIPTION (provided by applicant): Our proposal directly addresses the Program Announcement (RFA-AI-10-003) goals of "development of broad- spectrum (innate immunity) immunotherapeutic that targets NIAID Priority Agents" and establishment of "collaborations between researchers in different disciplines and/or with industry" in a very powerful and unique fashion. Here we will describe our extensive published data revealing the novel function of transcription factor hypoxia inducible factor-1 (HIF-1) as a master regulator of host innate immune function, including proof-of-principle demonstrations that pharmacologic targeting of HIF-1 can augment the bactericidal capacity of phagocytic cells against Gram+ and Gram- bacteria in vitro and in vivo. HIF-1 is induced by bacterial infection, even under normoxia, and regulates the production of key immune effector molecules including granule proteases, antimicrobial peptides, nitric oxide and TNF-a. We then provide exciting new unpublished data that show how potent new-generation prolyl hydroxylase (PHD) inhibitor drugs from Akebia Therapeutics, Inc. boost HIF-1 in human phagocytes and cause them to kill pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) with efficiency comparable to classical antibiotic therapy. Importantly, the same class of agents accelerates wound closing in skin, providing a therapeutic approach for skin and wound infections that promotes healing while simultaneously providing an anti-infective barrier. This innovative antimicrobial treatment strategy, working through the host, is inherently broad spectrum and can be used as an adjunct to classical antibiotic therapy. Rather than designing drugs to target the bacteria, medications that promote HIF-1a activity could be used to boost the bacterial killing ability of white blood cells and promote the resolution of infection through the actions of our natural immune defenses. The research plan will further establish the mechanistic underpinnings for HIF-1 antimicrobial activity by microarray and companion immunogenetic analysis of HIF-1 regulated genes in the context of infection, the role of HIF-1 in protecting against microbial toxin induced phagocyte toxicity and apoptosis, and the involvement of phagocyte extracellular traps in HIF-1 mediated bacterial killing. HIF-1 knockout mice will be used to assess the role of the transcriptional control pathway in control of MRSA and Pseudomonas infections in skin, skin wounds, and pneumonia models of infection. Then, as informed by the results of those studies, treatment trials of HIF-agonist lead compound AKB-4924 against MRSA and P. aeruginosa will be explored in these same models, with topical compared to systemic therapy in the skin and wound models. Through our partnership with Akebia Therapeutics, an extensive preclinical development plan of pharmacokinetic and safety/toxicity analyses will be conducted with the goal of an FDA Investigational New Drug Application for entry into clinical trials of bacterial skin infection, initial as a topical agent. Ultimately, HIF-1 immune boosting therapy could find wide application in the treatment of difficult infections complicated by antibiotic resistance or weakened host defense.

描述（由申请人提供）：我们的提案直接解决了“针对NIAID优先级代理的广阔频谱（先天免疫）免疫治疗剂的开发（RFA-AI-10-003）的目标”，并在不同学科和/或与/或具有非常强大和独特的行业的研究人员之间建立合作”。在这里，我们将描述我们广泛发表的数据，揭示了转录因子缺氧诱导因子-1（HIF-1）的新功能，作为宿主先天免疫功能的总体调节剂，包括原理证明的证明，HIF-1的药理学靶向HIF-1可以增强对涉及Gram+和Gram-bacteria Intro和Gram-bacteria Intro和Viv的吞噬细胞的细菌能力。 HIF-1是由细菌感染诱导的，即使在常氧下，也可以调节关键免疫效应分子的产生，包括颗粒蛋白酶，抗菌肽，一氧化氮和TNF-A。然后，我们提供令人兴奋的新的未发表数据，这些数据显示了来自Akebia Therapeutics，Inc。的有效的新代羟化羟化酶（PHD）抑制剂。重要的是，同一类代理会加速皮肤的伤口，为皮肤和伤口感染提供治疗方法，可促进愈合，同时提供抗感染屏障。通过宿主运行的这种创新的抗菌治疗策略本质上是广泛的，可以用作经典抗生素疗法的辅助。可以使用促进HIF-1A活性的药物来提高白细胞的细菌杀伤能力，并通过我们的天然免疫防御剂的作用来促进感染的分辨率，而不是设计药物以靶向细菌。该研究计划将进一步建立通过微阵列和HIF-1的免疫遗传学分析HIF-1调节基因在感染的背景下，HIF-1在保护微生物毒素诱导的吞噬细胞毒性和细菌的作用中，对HIF-1调节基因的机械基础，以及HIF-1的作用。 HIF-1基因敲除小鼠将用于评估转录控制途径在控制皮肤，皮肤伤口和肺炎感染模型中MRSA和假单胞菌感染中的作用。然后，正如这些研究的结果所示，在这些相同模型中，将探索HIF激动剂化合物AKB-4924对MRSA和铜绿假单胞菌的治疗试验，与皮肤和伤口模型中的全身治疗相比，具有局部治疗。通过与Akebia Therapeutics的合作关系，将进行广泛的药代动力学和安全性/毒性分析的临床前开发计划，以FDA研究新药申请进入细菌皮肤感染的临床试验，最初是作为局部药物的临床试验。最终，HIF-1免疫促进疗法可以在治疗抗生素耐药性或宿主防御弱化的困难感染中发现广泛的应用。