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Molecular basis of adenosine transport and reuptake inhibition in human

人体腺苷转运和再摄取抑制的分子基础

基本信息

批准号：
10549779
负责人：
Jiyong Hong
金额：
$ 40.66万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10549779
关键词：
Acceleration Address Adenosine Agonist Antihypertensive Agents Binding Biochemical Biological Assay Biological Models Biology Blood Cardiac Cell membrane Cells Cellular Membrane Chemicals Clinic Clinical Clinical effectiveness Complex Crystallography Cytosol Data Development Dipyridamole Engineering Equilibrative Nucleoside Transporter 1 Equilibrium Exhibits FDA approved Future G-Protein-Coupled Receptors Goals Half-Life Heart Heart Diseases Heart Transplantation Human Hybrids Hypoxia Infarction Intervention Intravenous Kidney Kidney Diseases Kidney Transplantation Knowledge Lung Lung Transplantation Lung diseases Mediating Membrane Membrane Transport Proteins Modeling Molecular Molecular Conformation Mutagenesis Myocardial Ischemia Nucleoside Transporter Nucleosides Organ Transplantation Organ failure Outcome Patients Property Protein Isoforms Purine Nucleosides Purinergic P1 Receptors Refractory Renal Tissue Reperfusion Injury Reperfusion Therapy Research Series Signal Transduction Specificity Structure Substrate Specificity Therapeutic Therapeutic Intervention Thioinosine Tissues Toxic effect Variant Work adenosine receptor activation adenosine transporter analog cardioprotection clinically relevant combat design experience experimental study extracellular improved inhibitor interest novel nucleoside analog organ transplant rejection pharmacologic pharmacophore prevent protective effect rational design response restoration reuptake side effect survival outcome therapeutic target vasoactive agent

项目摘要

Ischemia-reperfusion (IR) injury is a phenomenon in which hypoxic tissue undergoes prolonged damage after the return of oxygenated blood, proving a prevalent clinical challenge faced in organ transplant, and ischemic heart, lung and kidney diseases. Ultimately, IR injury can lead to increased infarct size, organ rejection and organ failure. The purine nucleoside adenosine is produced extracellularly in response to IR injury, and elicits cardioprotective, pulmonary protective and renal protective effects through agonizing adenosine G-protein coupled receptors. However, the half-life of extracellular adenosine is extremely short-lived, as specialized integral membrane transport proteins mediate the rapid membrane permeation of adenosine, where the nucleoside is ultimately metabolized within the cytosol. Human equilibrative nucleoside transporters (hENTs) are the main cellular adenosine transporters. Furthermore, adenosine reuptake inhibitors (AdoRIs), a chemically diverse class of hENT inhibitors, potentiate extracellular adenosine signaling by preventing its rapid reuptake through hENTs. Therefore, select AdoRIs are clinically used as vasoactive agents in the treatment of cardiopathy and renal disorders. However, current AdoRIs are limited in their clinical effectiveness due to their poor pharmacological properties and toxicities. Efforts to improve current AdoRIs or develop novel AdoRIs has been challenged by the lack of atomic-level information on hENTs and the mechanism of AdoRIs. This proposed research seeks to address this gap in knowledge by employing molecular, cellular, and chemical approaches to interrogate features of adenosine reuptake inhibition, adenosine recognition and the transport mechanism exhibited by hENTs. Notably, the rational design of novel adenosine reuptake inhibitors displaying improved subtype specificity will be pursued using cardiac and renal model systems. This work will uncover the molecular features of AdoRI activity, adenosine recognition, along with the transport mechanism exhibited by hENTs. In total, successful completion of this work will provide the framework for improved pharmacological intervention of adenosine biology, which will have far-reaching implications in the treatment of ischemic heart, lung, and kidney disease.

缺血再灌注（IR）损伤是机体缺氧后组织长期损伤的一种现象