Examining Carbon Monoxide to Treat Inflammatory Conditions using Experimental Colitis Models

使用实验性结肠炎模型检查一氧化碳治疗炎症的作用

基本信息

批准号：
10437776
负责人：
LEO E OTTERBEIN
金额：
$ 70.89万
依托单位：
GEORGIA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-10 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10437776
关键词：
Acute Animal Model Animals Anti-Inflammatory Agents Antiinflammatory Effect Area Bacterial Infections Carbon Monoxide Characteristics Clinical Clinical Trials Clostridium difficile Colitis Colon Cytoprotection Data Defect Dependence Development Disease Dose Drug Costs Drug Kinetics Foundations Functional disorder Funding Future Gases Goals Heme Hospitals Host Defense Human Immune Tolerance Immune response Immunomodulators Immunosuppression In Vitro Infection Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Inhalation Innate Immune Response Intestines Kinetics Lead Light Link Literature Mammals Medical Genetics Metals Modality Modeling Mucous Membrane Mus Myocardial Infarction Neoplasms Nitric Oxide Nobel Prize Oral Organ Transplantation Oxygenases Pathogenesis Pathogenicity Pharmaceutical Chemistry Pharmacologic Substance Pharmacology Pharmacology and Toxicology Photosensitivity Physiology Predisposition Prodrugs Property Publications Reperfusion Injury Reporting Research Resolution Respiratory physiology Sepsis Series Signaling Molecule Stroke T-Lymphocyte Testing Therapeutic Therapeutic Effect Time Toxicology United States National Institutes of Health Work base clinical translation design dosage drug development drug discovery dysbiosis effective therapy gut inflammation gut microbiota immunoregulation improved in vivo indexing individual patient infection risk innovation interdisciplinary approach liver injury macrophage metal poisoning mouse model novel pathogenic bacteria portability pre-clinical prevent protective effect repaired tissue injury tissue repair tool

项目摘要

Abstract Carbon monoxide (CO) is an endogenous signaling molecule with importance on par with nitric oxide (NO), the subject of the 1998 Nobel Prize. It is produced from heme degradation by heme oxygenases. Extensive literature reports have convincingly demonstrated the therapeutic effects of CO as an anti-inflammatory agent in models of colitis, sepsis, liver injury, and organ transplant. While much is known regarding the efficacy of CO, the challenge now is to develop pharmaceutically acceptable deliverable forms of CO as research tools and possible therapeutics. Inhaled CO has been the major form of delivery in most preclinical work. However, this is not the ideal modality because of difficulties in safe administration and in controlling doses, lack of portability, and the dependence on each individual patient’s respiratory function to deliver precise amounts. There have also been a number of metal-based CO-releasing molecules (CO-RMs) and photo-sensitive organic CO-RMs. However, metal toxicity and light accessibility issues impose limitations. In an exciting development, we have developed several classes of organic CO-prodrugs with tunable release rates. We propose to explore the potential of using such prodrugs to treat inflammation and tissue injury using experimental colitis (EC) in mice as a model. Others and we have demonstrated the unique ability of CO to reduce inflammation, promote tissue repair, and enhance host defense against pathogenic bacterial infection. Therefore, CO has enormous potential to be an effective treatment for colitis without the increased risk of infection associated with broad immunosuppression. With the high cost of drug discovery and development which is way beyond the funds available in an NIH application, we plan to initially examine a well-defined set of issues. The availability of prodrugs with tunable release rates offers the opportunity for the first time to examine the interplay among dosage, efficacy, pharmacokinetics, and release profiles, which is a unique problem with a gasotranmistter. In this MPI application, we combine the extensive expertise of the Wang, Tan, and Otterbein labs, and propose to build on compelling preliminary data to develop organic CO-prodrugs for treating inflammation in EC models. Our central hypothesis is that CO-prodrugs acts therapeutically in EC by modulating the intestinal microenvironment. We will test this with the following 2 specific aims: 1.) synthesize, optimize, and assess CO prodrugs; and 2.) evaluate the CO-prodrugs in EC. Our preliminary results clearly show efficacy of such CO-prodrugs in treating murine EC, sepsis, and liver injury. Upon completion of the project, we expect to have: 1.) developed a series of CO prodrugs, 2.) demonstrated the feasibility of using such prodrugs to treat inflammation in EC models; and (3) defined the relationship among dose, release kinetics, pharmacokinetics and efficacy with a clear therapeutic window. The clinical potential of CO-based therapeutics as anti-inflammatory agents is profound and could impact other areas such as organ transplantation, stroke, and heart attack.

抽象的一氧化碳 (CO) 是一种内源性信号分子，其重要性与一氧化氮 (NO) 相当，而一氧化氮 (NO) 是 1998 年诺贝尔奖的主题是由血红素加氧酶降解产生。文献报告令人信服地证明了 CO 作为抗炎剂的治疗效果在结肠炎、脓毒症、肝损伤和器官移植模型中，虽然人们对它的功效知之甚少。 CO，现在的挑战是开发药学上可接受的可交付形式的 CO 作为研究工具吸入 CO 是大多数临床前工作的主要给药方式。这不是理想的方式，因为安全给药和控制剂量方面存在困难，缺乏便携性，以及依赖每个患者的呼吸功能来提供精确的量。还出现了许多金属基CO释放分子（CO-RM）和光敏材料然而，有机 CO-RM 的金属毒性和光可及性问题带来了限制。在开发过程中，我们开发了几类具有可调释放速率的有机复合前药。建议探索使用此类前药治疗炎症和组织损伤的潜力我们和其他人以小鼠实验性结肠炎（EC）为模型，证明了 CO 的独特能力。减少炎症，促进组织修复，增强宿主对病原菌感染的防御能力。因此，CO 具有成为结肠炎有效治疗方法的巨大潜力，且不会增加结肠炎的风险。与广泛的免疫抑制相关的感染与药物发现和开发的高成本有关。这远远超出了 NIH 申请中可用的资金，我们计划首先检查一组明确定义的释放速率可调的前药的出现为我们提供了首次研究的机会。剂量、功效、药代动力学和释放曲线之间的相互作用，这是药物治疗的一个独特问题在这个 MPI 应用中，我们结合了 Wang、Tan 和 Otterbein 的丰富专业知识。实验室，并建议以令人信服的初步数据为基础，开发用于治疗的有机复合前药 EC 模型中的炎症。我们的中心假设是 CO-前药通过以下方式在 EC 中发挥治疗作用：我们将通过以下两个具体目标来测试这一点：1.) 合成，优化并评估 CO 前药；2.) 清楚地评估 EC 中的 CO 前药。完成实验后，显示了此类 CO-前药在治疗小鼠 EC、脓毒症和肝损伤中的功效。项目中，我们期望：1.）开发一系列CO前药，2.）证明使用的可行性这些前药在 EC 模型中治疗炎症；(3) 确定了剂量、释放之间的关系；基于 CO 的动力学、药代动力学和疗效具有明确的治疗窗口。作为抗炎剂的疗法意义深远，可能会影响器官等其他领域移植、中风和心脏病。