A2B receptor stimulation for sepsis

A2B 受体刺激治疗脓毒症

• 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
• 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

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.

摘要 脓毒症是一种由感染引起的压倒性全身炎症反应引起的内科疾病。 尽管潜在的感染现在可以用抗生素有效地治疗，但还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 是重症监护病房的主要死亡原因，是美国第十大主要死亡原因。胞外 腺苷是一种生物活性的信号分子，在脓毒症的代谢应激部位聚集。 胞外腺苷通过与G蛋白偶联的A2B结合并激活而具有强大的抗炎作用 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A2BARs可以保护小鼠免受多菌体引起的败血症。 炎症、器官损伤和死亡。基于这些结果，我们假设药理学上 A2BARs的刺激通过抑制炎症来保护败血症死亡率和器官损伤。致信地址 在这一假设下，我们将研究我们开发的两种新型、有效和选择性的A2BAR激动剂P453的疗效 和P517，逆转败血症死亡率、炎症和器官功能障碍。该提案的具体目的 具体目的：1.评价P453和P517对脓毒症小鼠死亡率的影响。具体目标2.划定 P453和P517在脓毒症小鼠炎症和器官损伤中的作用因此，这项建议推进了 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。