A2B receptor stimulation for sepsis

A2B 受体刺激治疗脓毒症

基本信息

批准号：
10545455
负责人：
George HASKO
金额：
$ 22.63万
依托单位：
PURINE PHARMACEUTICALS, INC.
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：
2022-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10545455
关键词：
ADORA3 gene Address Adenosine Adenosine A2B Receptor Adenosine A3 Receptor Adenosine Triphosphate Agonist Anti-Inflammatory Agents Antibiotics Antiinflammatory Effect Bacteria Binding Brain Hypoxia-Ischemia Burn injury Cause of Death Cell Death Cell surface Cells Clinical Clinical Research Coupled Critical Illness Dose Endothelial Cells Extracellular Space FDA approved Functional disorder GTP-Binding Proteins Goals Growth HMGB1 Protein Heat shock proteins Histology Host Defense Hyaluronan Hypotension Immune Immune response Immune system Infection Inflammation Inflammation Process Inflammatory Inflammatory Response Innate Immune System Intensive Care Units Mediating Medical Medicine Metabolic Metabolic stress Molecular Morbidity - disease rate Mus Organ Organ failure Patients Pattern Pharmacology Population Purine Nucleosides Purine Nucleotides Purinergic P1 Receptors Reporting Research Role Sepsis Signal Pathway Signal Transduction Signaling Molecule Site Surface Syndrome Systemic disease Testing Therapeutic Intervention Time Tissues Trauma Uric Acid Vasodilation antagonist base cecal ligation puncture clinically relevant effective therapy efficacy study extracellular immune activation immunoregulation mortality novel novel therapeutics organ injury pathogen pneumonia model polymicrobial sepsis prevent receptor response septic systemic inflammatory response transcription factor

项目摘要

SUMMARY Sepsis is a medical condition caused by an overwhelming systemic inflammatory response to infection. Although the underlying infection can now be efficiently treated with antibiotics, there are no effective therapies to control the organ damage caused by the inflammatory response of the host. As a result, sepsis is the leading cause of mortality in intensive care units and is the tenth leading cause of death overall in the US. Extracellular adenosine is a biologically active signaling molecule that accumulates at sites of metabolic stress in sepsis. Extracellular adenosine has potent anti-inflammatory effects by binding to and activating G protein-coupled A2B adenosine receptors (ARs) on the surface of immune and endothelial cells. Using A2BAR deficient mice and pharmacological antagonists, we have discovered that A2BARs protect mice against polymicrobial sepsis-induced inflammation, organ damage, and mortality. Based on these results, we hypothesize that pharmacological stimulation of A2BARs protects against septic mortality and organ injury by suppressing inflammation. To address this hypothesis, we will study the efficacy of two novel, potent and selective A2BAR agonists we developed, P453 and P517, in reversing septic mortality, inflammation, and organ dysfunction. The Specific Aims of the proposal are: Specific Aim 1. Assess the effect of P453 and P517 on mortality in murine sepsis. Specific Aim 2. Delineate the effect of P453 and P517 on inflammation and organ injury in murine sepsis. This proposal thus advances new therapeutic applications to control and/or alleviate sepsis-induced organ injury and mortality.

概括脓毒症是一种由对感染的强烈全身炎症反应引起的疾病。虽然现在可以用抗生素有效治疗潜在的感染，但没有有效的治疗方法控制宿主炎症反应引起的器官损伤。因此，败血症是最主要的是重症监护病房的死亡原因，也是美国第十大死亡原因。细胞外腺苷是一种生物活性信号分子，在脓毒症代谢应激部位积聚。细胞外腺苷通过结合并激活 G 蛋白偶联 A2B 具有有效的抗炎作用免疫细胞和内皮细胞表面的腺苷受体（AR）。使用 A2BAR 缺陷小鼠和药理拮抗剂，我们发现 A2BAR 可以保护小鼠免受多种微生物引起的败血症炎症、器官损伤和死亡。基于这些结果，我们假设药理学刺激 A2BAR 可通过抑制炎症来预防败血症死亡和器官损伤。致地址根据这一假设，我们将研究我们开发的两种新型、强效和选择性 A2BAR 激动剂 P453 的功效和 P517，可逆转脓毒症死亡率、炎症和器官功能障碍。该提案的具体目标具体目标 1. 评估 P453 和 P517 对小鼠脓毒症死亡率的影响。具体目标 2. 描绘 P453 和 P517 对小鼠脓毒症炎症和器官损伤的影响。因此，该提案提出了控制和/或减轻脓毒症引起的器官损伤和死亡率的新治疗应用。