Soluble E-NTPDase for sepsis

用于败血症的可溶性 E-NTPDase

基本信息

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
项目类别：
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&apos -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

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. 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.

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。这外核苷三磷酸二磷酸水解酶 (E-NTPDase) CD39 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并触发抗炎分子的产生剂腺苷。我们发现内源性 CD39 可以保护小鼠免受多种微生物败血症的侵害导致死亡、器官损伤和炎症。同样，注射可溶性 E-NTPDase/CD39 模拟物（腺苷三磷酸双磷酸酶）具有保护作用。基于这些结果，我们建议外源施用可溶性 E-NTPDase 作为一种新颖有效的脓毒症治疗方法。然而，腺苷三磷酸双磷酸酶（一种植物来源的 E-NTPDase/CD39 模拟物）很可能在人体中引发危险的抗体反应，从而阻止其用作脓毒症的治疗剂患者。为了克服这个问题，在当前的提案中，我们将评估优化人类的效果脓毒症中的重组可溶性 E-NTPDase (APT102)。我们的假设是 APT102 会降低死亡率，器官损伤和脓毒症炎症。为了解决这个假设，我们提出了两个具体目标。具体来说目标 1，我们将测试 APT102 在预防盲肠引起的多种微生物败血症死亡方面的功效小鼠结扎和穿刺。在具体目标 2 中，我们将描述 APT102 对器官损伤和脓毒症中的炎症。我们预计 APT102 将降低脓毒症患者的死亡率、器官损伤和炎症老鼠。本研究的长期目标是开发 APT102 作为一种安全有效的治疗选择败血症患者的管理。