Recombinant E-NTPDase for shock

用于休克的重组 E-NTPDase

基本信息

批准号：
10757117
负责人：
George HASKO
金额：
$ 30万
依托单位：
PURINE PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-21 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10757117
关键词：
5&apos -Nucleotidase Acute Lung Injury Acute Respiratory Distress Syndrome Address Adenosine Adenosine Diphosphate Adenosine Monophosphate Adenosine Triphosphate Alkaline Phosphatase Anti-Inflammatory Agents Antibody Response Antigens Apyrase Blood Pressure Blood flow Cell Surface Receptors Cell surface Cells Cessation of life Data Detection Dose Enzymes Erythrocytes Extracellular Space Family Genetic Goals Hemorrhage Hemorrhagic Shock Human Hypovolemic Shock IV Fluid Immune System Diseases Immune system Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injections Injury Ischemia Kidney Knock-out Laparotomy Liver Lung Modeling Molecular Morbidity - disease rate Multiple Organ Failure Mus Muscle Organ Outcome Pathway interactions Patients Physiological Potato Purinergic P1 Receptors Purinergic P2 Receptors Receptor Activation Receptor Signaling Recombinants Reperfusion Injury Reporting Resuscitation Role Secondary to Selectins Sepsis Shock Signal Transduction Signaling Molecule Surface Syndrome System Systemic Inflammatory Response Syndrome Testing Therapeutic Agents Therapeutic Intervention Trauma Trauma patient United States cell injury cytokine ectoADPase effective therapy efficacy testing extracellular functional outcomes immune function immunoregulation ischemic injury member mortality mouse model novel novel therapeutics organ injury pharmacologic phosphoric diester hydrolase prevent pyrophosphatase receptor systemic inflammatory response therapeutically effective tripolyphosphate

项目摘要

SUMMARY Inflammation after ischemia and reperfusion injury secondary to hemorrhagic shock is responsible for significant mortality and morbidity in the United States. Available intravenous fluids administered at the incident scene to treat hypovolemic shock do not completely prevent ischemia and reperfusion injury. Re-initiation of blood flow causes activation of several inflammatory mediators, such as cytokines, selectins and other molecules that rapidly mobilize the inflammatory response with subsequent multiple organ failure. The goal of the proposed project is to prevent or reduce the deleterious effects of ischemic damage following resuscitation by using a soluble recombinant human ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) in conjunction with intravenous fluids in patients with hemorrhagic shock. The approach is based on the well-documented physiological protective role of E-NTPDases in protecting against ischemia-reperfusion injury. Our preliminary data confirm that the endogenous E-NTPDase CD39 and the exogenously administered E-NTPDase mimic apyrase both prevent organ injury in a well-accepted mouse model of fixed blood pressure shock. We have synthesized a novel, highly potent E-NTPDase, hENTPD3-ECD, which we will test for efficacy in preventing organ injury following trauma and hemorrhagic shock. The specific aim of this proposal is to assess the effect of hENTPD3-ECD on organ injury in hemorrhagic shock. A dose-escalation study will be conducted with hENTPD3- ECD in mice subjected to a combined insult of laparotomy (trauma) and hemorrhagic shock. These studies will establish the effective dose of hENTPD3-ECD in protecting against organ injury in trauma and hemorrhagic shock. Outcomes reported will be lung, gut, kidney, liver, and muscle injury, and red blood cell injury and immune function. This proposal advances new therapeutic applications to control and/or alleviate ischemia/reperfusion injury during and following resuscitation from shock.

概括继发于失血性休克的缺血和再灌注损伤后的炎症是导致美国的死亡率和发病率很高。事件发生时可用的静脉输液现场治疗低血容量性休克并不能完全防止缺血再灌注损伤。重新启动血流引起多种炎症介质的激活，例如细胞因子、选择素和其他分子迅速引发炎症反应，导致随后的多器官衰竭。拟议的目标该项目的目的是通过使用以下方法来预防或减少复苏后缺血性损伤的有害影响可溶性重组人外核苷三磷酸二磷酸水解酶 (E-NTPDase) 与失血性休克患者的静脉输液。该方法基于有据可查的 E-NTPDases 在防止缺血再灌注损伤中的生理保护作用。我们的初步数据证实内源性 E-NTPDase CD39 和外源性施用的 E-NTPDase 模拟物在广为接受的固定血压休克小鼠模型中，腺苷三磷酸双磷酸酶均可预防器官损伤。我们有合成了一种新型、高效的 E-NTPDase，hENTPD3-ECD，我们将测试其预防的功效外伤和失血性休克后的器官损伤。该提案的具体目的是评估 hENTPD3-ECD 对失血性休克器官损伤的影响。将使用 hENTPD3- 进行剂量递增研究遭受剖腹手术（创伤）和失血性休克联合损伤的小鼠的 ECD。这些研究将确定 hENTPD3-ECD 预防创伤和出血性器官损伤的有效剂量震惊。报告的结果将是肺、肠、肾、肝和肌肉损伤，以及红细胞损伤和免疫功能。该提案推进了控制和/或减轻缺血/再灌注的新治疗应用休克复苏期间和之后的伤害。