Soluble E-NTPDase for sepsis

用于败血症的可溶性 E-NTPDase

• 批准号: 9253962
• 负责人: George HASKO
• 金额: $ 22.49万
• 依托单位: PURINE PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-11 至 2019-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9253962
• 关键词: 5' -Nucleotidase; Address; Adenosine; Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Alkaline Phosphatase; Alpha Cell; Amino Acid Substitution; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Antibody Response; Antigens; Apyrase; Body part; Cause of Death; Cell Surface Receptors; Cell surface; Cells; Cessation of life; Clinical; Critical Illness; Detection; Dose; Enzymes; Extracellular Space; Family; Genetic; Goals; Histology; Human; Immune response; Immune system; Infection; Inflammation; Inflammatory; Inflammatory Response; Injectable; Injection of therapeutic agent; Injury; Intensive Care Units; Knock-out; Ligation; Medical; Modeling; Molecular; Morbidity - disease rate; Mus; Organ; Organ failure; Pathway interactions; Patients; Pharmacology; Plants; Population; Potato; Production; Puncture procedure; Purinergic P1 Receptors; Purinergic P2 Receptors; Receptor Activation; Receptor Signaling; Recombinants; Reporting; Role; Sepsis; Shock; Signal Transduction; Signaling Molecule; Sterility; Surface; System; Testing; Therapeutic Agents; Therapeutic Intervention; Time; Treatment Efficacy; adenosine monophosphate-adenosine; base; cytokine; ectoADPase; effective therapy; efficacy testing; extracellular; immunoregulation; member; microbial; mortality; novel therapeutics; organ growth; phosphoric diester hydrolase; prevent; pyrophosphatase; receptor; septic; transcription factor; tripolyphosphate

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. The ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) CD39 is a cell surface-associated anti- inflammatory enzyme. It has multiple anti-inflammatory actions, which include degradation of the endogenous proinflammatory molecule adenosine triphosphate and triggering of the production of the anti-inflammatory agent adenosine. We have discovered that endogenous CD39 protects mice against polymicrobial sepsis- induced mortality, organ damage, and inflammation. Similarly, injecting a soluble E-NTPDase/CD39 mimic (apyrase) is protective. Based on these results, we propose exogenously administered soluble E-NTPDase as a novel and effective therapy for sepsis. However, apyrase, an E-NTPDase/CD39 mimic of plant origin, is likely to provoke a hazardous antibody response in humans preventing its use as a therapeutic agent for septic patients. To overcome this problem, in the current proposal we will evaluate the effect of an optimized human recombinant soluble E-NTPDase (APT102) in sepsis. Our hypothesis is that APT102 would reduce mortality, organ injury, and inflammation in sepsis. To address this hypothesis, we propose two Specific Aims. In Specific Aim 1, we will test the efficacy of APT102 in preventing mortality in polymicrobial sepsis induced by cecal ligation and puncture in mice. In Specific Aim 2, we will delineate the effect of APT102 on organ injury and inflammation in sepsis. We expect that APT102 will reduce mortality, organ injury, and inflammation in septic mice. The long-term goal of this study is to develop APT102 as a safe and effective treatment option for the management of patients with sepsis.

总结 脓毒症是由对感染的压倒性全身炎症反应引起的医学病症。 虽然现在可以用抗生素有效地治疗潜在的感染，但没有有效的治疗方法 以控制由宿主的炎症反应引起的器官损伤。因此，败血症是 是重症监护病房死亡的主要原因，也是美国第十大死亡原因。的 胞外核苷三磷酸二磷酸水解酶（E-NTPDase）CD 39是一种细胞表面相关的抗- 炎症酶。它具有多种抗炎作用，包括降解内源性 促炎分子三磷酸腺苷和触发抗炎物质的产生 腺苷探员我们已经发现内源性CD 39保护小鼠免受多微生物败血症- 诱发死亡、器官损伤和炎症。类似地，注射可溶性E-NTPD酶/CD 39模拟物 （腺苷三磷酸双磷酸酶）是保护性的。基于这些结果，我们建议外源性给予可溶性E-NTPD酶作为 一种新的有效的治疗脓毒症的方法。然而，腺苷三磷酸双磷酸酶，一种植物来源的E-NTPD酶/CD 39模拟物， 在人体中引起有害的抗体反应，从而阻止其用作脓毒性的治疗剂， 患者为了克服这个问题，在目前的提案中，我们将评估一个优化的人的效果， 重组可溶性E-NTPD酶（APT 102）在脓毒症中的作用。我们的假设是APT 102可以降低死亡率， 器官损伤和败血症中的炎症。为了解决这个问题，我们提出了两个具体目标。在特定 目的1，我们将测试APT 102在预防盲肠炎诱导的多微生物脓毒症中的死亡率的功效。 结扎和穿刺。在具体目标2中，我们将描述APT 102对器官损伤的影响， 脓毒症中的炎症我们预计，APT 102将减少败血症患者的死亡率、器官损伤和炎症。 小鼠本研究的长期目标是开发APT 102作为一种安全有效的治疗选择， 脓毒症患者的管理。