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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.

项目总结/文摘