Directing Tryptophan Immunometabolism to Ameliorate Liver Ischemic-Reperfusion Injury

指导色氨酸免疫代谢改善肝脏缺血再灌注损伤

• 批准号: 10595020
• 负责人: Benjamin George Keselowsky
• 金额: $ 65.42万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595020
• 关键词: Acute; Address; Anti-Inflammatory Agents; Antibodies; Antigens; Automobile Driving; Biological; Blood Circulation; Blood flow; Catalogs; Cell Death; Cell physiology; Cells; Chronic; Circulation; Clinical; Coupled; Data; Disease; Dose; Drug Kinetics; Engraftment; Enzymes; Essential Amino Acids; Formulation; Future; Goals; Half-Life; Homeostasis; Immune; Immune response; Immunocompromised Host; Immunophenotyping; Immunosuppression; In Vitro; Incidence; Inflammation; Inflammatory; Injectable; Injections; Injury; Ischemia; Kynurenine; Left; Liquid substance; Liver; Liver Dysfunction; Liver Failure; Maximum Tolerated Dose; Mediator; Metabolic; Metabolism; Myocardial Infarction; Operative Surgical Procedures; Organ; Organ failure; Outcome; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacodynamics; Polyethylene Glycols; Positioning Attribute; Process; Reperfusion Injury; Site; Sterility; Stroke; Technology; Therapeutic; Tissues; Toxic effect; Toxicology; Transplantation; Trauma; Tryptophan; Tryptophan 2,3 Dioxygenase; Tryptophan Metabolism Pathway; Vascular blood supply; cell injury; cell type; clinical practice; cytotoxicity; drug action; druggable target; extracellular; immunogenicity; immunoregulation; implantation; in vivo; innovation; interest; intravenous administration; liver ischemia; novel therapeutic intervention; novel therapeutics; preconditioning; preservation; programs; prophylactic; restoration; side effect; success; systemic toxicity; tissue repair

Project Summary/Abstract Many different disease states and surgical interventions result in a period of inadequate tissue/organ blood supply (i.e., ischemia), that result in reperfusion injury when blood flow is restored, known as ischemia-reperfusion injury (IRI). IRI causes local inflammation, cell death, excessive tissue destruction and possible organ failure. Examples are found in transplantation, trauma, myocardial infarction, stroke, and in particular, IRI is a main cause of liver dysfunction and failure after liver surgery. Unfortunately, there are currently no therapies available in clinical practice addressing IRI, where a major problem is the harmful systemic side effects and toxicities of existing drugs. To address this problem, we are innovating a new therapeutic technology aiming to program immune cells toward a metabolic state blocking excessive inflammation by directing tryptophan metabolism through delivery of an enzyme into circulation. This represents a new class of anti- inflammatory/immunosuppressive biologic drug, with potential to limit systemic toxicities/side effects, and with potential to be significantly less immunocompromising. Lack of treatment options for liver IRI and a catalog of in vivo preliminary data strongly supporting the foundational rationale of IDO as an innovative new anti-inflammatory agent, make this proposal highly significant. Looking to the future, success would open opportunity to expand to other anti-inflammatory applications, for example, pre-conditioning donor grafts for transplantation.

项目总结/摘要 许多不同的疾病状态和手术干预导致一段时间的不充分 组织/器官血液供应（即，缺血），当血流被阻断时， 恢复，称为缺血再灌注损伤（IRI）。IRI导致局部炎症细胞死亡， 过度的组织破坏和可能的器官衰竭例如在移植中， 创伤、心肌梗塞、中风，特别是IRI是肝功能障碍的主要原因 以及肝脏手术后的衰竭不幸的是，目前临床上没有可用的治疗方法。 处理IRI的实践，其中一个主要问题是有害的全身副作用和毒性 现有的药物。 为了解决这个问题，我们正在创新一种新的治疗技术， 通过引导色氨酸，免疫细胞进入代谢状态， 通过将酶输送到循环中进行新陈代谢。这代表了一种新的反- 炎症/免疫抑制生物药物，可能限制全身毒性/副作用 效果，并且具有显著降低免疫妥协的潜力。缺乏治疗选择 对于肝脏IRI和一个强烈支持基本原理的体内初步数据目录 IDO作为一种创新的新型抗炎剂，使这一建议非常重要。 展望未来，成功将打开机会，扩大到其他抗炎药 例如，预处理供体移植物用于移植。