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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.

总结