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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要许多不同的疾病状态和手术干预会导致一段时期的不充分治疗组织/器官血液供应（即缺血），当血流不足时会导致再灌注损伤恢复，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。例子可以在移植中找到，外伤、心肌梗死、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失败。不幸的是，目前临床上还没有可用的治疗方法实践解决IRI，其中一个主要问题是有害的系统副作用和毒性现有药物。为了解决这个问题，我们正在创新一种新的治疗技术，旨在编程免疫细胞通过引导色氨酸进入代谢状态来阻止过度炎症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，有可能限制全身毒性/副作用效应，并且有可能显着减少免疫损害。缺乏治疗选择肝脏 IRI 和体内初步数据目录有力地支持了基本原理 IDO作为一种创新的新型抗炎剂的出现，使这一提议具有非常重要的意义。展望未来，成功将为扩展到其他抗炎药领域提供机会应用，例如，用于移植的供体移植物的预处理。