Novel Peptides for Resuscitation

用于复苏的新型肽

基本信息

批准号：
9913582
负责人：
HENRY R HALPERIN
金额：
$ 73.85万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9913582
关键词：
Affect Amino Acids Anatomy Back Binding Biological Biological Markers Blood Blood Circulation Brain C-terminal Caliber Cardiopulmonary Resuscitation Cause of Death Cells Cerebrovascular Circulation Clinical Combined Modality Therapy Development Dose Electric Countershock Extracorporeal Membrane Oxygenation Family suidae Glucose Glutamates HIV Heart Heart Arrest Hour Human Injury Intravenous Link Malignant neoplasm of lung Measurement Mediating Membrane Metabolic Modeling Mus Nerve Sheaths Neurologic Optic Nerve Organ Outcome PDPK1 gene Patients Peptides Perfusion Permeability Pharmaceutical Preparations Pharmacology Phosphoric Monoester Hydrolases Physiology Public Health Recovery Resuscitation Role Signal Transduction Sorbitol Stress Stroke Supplementation Survival Rate Taurine Testing Therapeutic Ultrasonography United States Ventricular Work comparative efficacy compare effectiveness design heart function improved inhibitor/antagonist intravenous administration malignant breast neoplasm natural hypothermia novel novel therapeutics pre-clinical preclinical study predictive marker pyruvate dehydrogenase tat Protein translational model

项目摘要

Sudden cardiac arrest (SCA) is a leading cause of death in the United States. It affects over 500,000 people annually with an overall survival rate of 7%. Unlike other leading causes of death, no pharmacological drugs exist to improve SCA survival. Cooling a few degrees Celsius during cardiopulmonary resuscitation (CPR) in pre-clinical studies is highly protective against SCA injury and appears mediated by enhanced Akt signaling. However, CPR cooling is difficult to physically implement clinically. Development of new CPR drugs that mimic cooling protection without the need for physical cooling could be highly effective and translational. Proposed work uses two novel cell-permeable peptides designed to inhibit PHLPP phosphatase (TAT-PHLPP9c) and to activate PDK1 (TAT-PIF) respectively. They reach critical organs such as heart and brain in less than 5 min when administering to the mouse intravenously and synergistically improve 4 h SCA survival after prolonged 12 min asystole cardiac arrest. Preliminary work in swine demonstrates that intravenous administration of TAT- PHLPP9c during CPR rapidly improves recovery of cardiac function after ROSC and significantly improves 24 hour neurologically intact survival after 5 min ventricular defibrillation (VF). We hypothesize that CPR administration of TAT-PHLPP9c and TAT-PIF collaboratively induce a rapid and maximal activation of Akt, subsequently enhances PDH activity, reduces glucose shunting to sorbitol, and enhances glucose utilization leading to an early replenishment of energy, diminished osmotic injury and release of taurine and glutamate into blood, and improved cardiac function and neurologically intact survival. This proposal will take systematic efforts to test a novel therapeutic strategy and their mechanisms of action by intravenously administration of cell-permeable peptides (TAT-PHLPP9c and TAT-PIF) during CPR following cardiac arrest in mouse, and swine, and further validate biomarkers and a non-invasive measurement of optic nerve sheath diameter (ONSD) to predict SCA outcome in human as illustrated in the following three aims. Aim 1. Determine whether TAT-PHLPP9c, a novel biological inhibitor of PHLPP phosphatase, and TAT-PIF, a novel biological activator of PDK1, improves SCA survival in a prolonged arrest (12 min) mouse SCA model. Aim 2. Determine whether these novel peptides improve swine SCA survival when given intravenously during CPR and compare the efficacy of these peptides to active cooling and ECMO therapies for SCA. Aim 3. Test biomarkers (taurine and glutamate) of osmotic stress and metabolic recovery with ultrasound measurement of osmotic stress-related ONSD to predict SCA outcome. Swine and human have a number of similarities in anatomy and physiology, therefore swine has been widely accepted as a highly translational model in testing therapies. If these two peptides can work as cooling and bring dead swine back after SCA, they have a high possibility to work in the human as cooling without a need to physically cool the patients which would be a major advance in SCA resuscitation.

心脏骤停（SCA）是美国的一个主要原因。它影响了超过 500,000 人每年，总生存率为 7%。与其他导致死亡的主要原因不同，没有药物存在以提高 SCA 存活率。心肺复苏 (CPR) 期间降温几摄氏度临床前研究对 SCA 损伤具有高度保护作用，并且似乎是通过增强的 Akt 信号传导介导的。然而，心肺复苏冷却在临床上很难实际实施。开发模仿 CPR 的新药物无需物理冷却的冷却保护可能非常有效且具有转化性。建议的该工作使用两种新型细胞渗透性肽，旨在抑制 PHLPP 磷酸酶 (TAT-PHLPP9c) 并分别激活PDK1 (TAT-PIF)。它们在 5 分钟内到达心脏和大脑等关键器官当对小鼠进行静脉注射时，可协同改善延长 12 小时后 4 小时的 SCA 存活率分钟心搏停止心脏骤停。对猪的初步研究表明，静脉注射 TAT- PHLPP9c 在 CPR 期间迅速改善 ROSC 后心功能的恢复并显着改善 24 5 分钟心室除颤 (VF) 后 1 小时神经系统完整存活。我们假设心肺复苏 TAT-PHLPP9c 和 TAT-PIF 协同给药可诱导快速、最大程度的激活 Akt 随后增强 PDH 活性，减少葡萄糖分流至山梨醇，并增强葡萄糖利用导致能量的早期补充、渗透损伤的减少和牛磺酸的释放和谷氨酸进入血液，改善心脏功能和神经系统完整的存活率。这个提议将采取系统的努力，通过静脉注射来测试一种新的治疗策略及其作用机制在心脏骤停后的心肺复苏过程中施用细胞渗透性肽（TAT-PHLPP9c 和 TAT-PIF）小鼠和猪，并进一步验证生物标志物和视神经鞘的非侵入性测量直径（ONSD）来预测人类 SCA 结果，如以下三个目标所示。目的 1. 确定 TAT-PHLPP9c（一种新型 PHLPP 磷酸酶生物抑制剂）和 TAT-PIF（一种新型 PHLPP 磷酸酶生物抑制剂）是否 PDK1 的新型生物激活剂，可提高长时间停滞（12 分钟）小鼠 SCA 模型中的 SCA 存活率。目标 2. 确定这些新型肽在猪 SCA 期间静脉注射时是否可以提高猪的 SCA 存活率心肺复苏 (CPR) 并比较这些肽与主动降温和 ECMO 治疗 SCA 的疗效。目标 3. 用超声波测试渗透压和代谢恢复的生物标志物（牛磺酸和谷氨酸）测量渗透压相关的 ONSD 来预测 SCA 结果。猪与人类在解剖学和生理学上有许多相似之处，因此猪被广泛被认为是测试疗法的高度转化模型。如果这两种肽能起到清凉、带来死猪在 SCA 后返回，它们很有可能在人体中发挥冷却作用，而不需要对患者进行物理降温，这将是 SCA 复苏的重大进步。