Novel Peptides for Resuscitation

用于复苏的新型肽

• 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
• 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

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.

在美国，心脏骤停(SCA)是主要的死亡原因。它影响了50多万人 年总存活率为7%。与其他主要死因不同，没有药理药物 存在于提高SCA存活率。在心肺复苏(CPR)期间降温几摄氏度 临床前研究对SCA损伤具有高度的保护作用，似乎是由增强的Akt信号介导的。 然而，CPR降温在临床上难以物理实施。模拟心肺复苏的新型药物的开发 不需要物理冷却的冷却保护可以是非常有效和可转换的。建议 Work使用了两种新的细胞通透性多肽，旨在抑制PHLPP磷酸酶(TAT-PHLPP9c)和 分别激活PDK1(TAT-PIF)。它们在不到5分钟的时间内到达心脏和大脑等关键器官 小鼠静脉给药协同作用延长12小时后4小时SCA存活 最小心跳停止。在猪身上的初步研究表明，静脉注射TAT- 心肺复苏术中PHLPP9c能迅速促进心功能恢复，显著改善心功能 室性除颤(VF)5分钟后1小时神经功能完整存活。我们假设心肺复苏 联合应用TAT-PHLPP9c和TAT-PIF可快速最大限度地激活 AKT，随后增强PDH活性，减少葡萄糖向山梨醇的分流，并提高血糖 利用能提前补充能量，减少渗透损伤和牛磺酸的释放 和谷氨酸进入血液，并改善心脏功能和神经完整的存活率。这项建议 将采取系统的努力，通过静脉注射测试一种新的治疗策略及其作用机制 心脏骤停心肺复苏期间细胞通透性多肽(TAT-PHLPP9c和TAT-PIF)的应用 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)用于预测人类SCA结果，如以下三个目标所示。 目的1.测定一种新型PHLPP磷酸酶生物抑制剂TAT-PHLPP9c和TAT-PIF对PHLPP磷酸酶活性的影响 新型生物激活剂PDK1，改善长时间停滞(12分钟)小鼠SCA模型的存活。 目的2.确定这些新的多肽是否提高了猪SCA的存活率 CPR，并将这些多肽与主动降温和ECMO治疗SCA的疗效进行比较。 目的3.超声检测渗透应激和代谢恢复的生物标志物(牛磺酸和谷氨酸) 测量渗透应激相关的ONSD以预测SCA结果。 猪和人类在解剖和生理上有许多相似之处，因此猪被广泛地 在测试疗法中被公认为高度翻译的模型。如果这两种多肽能够起到降温和带来 死猪回来后，它们有很高的可能性在人类工作时降温，而不需要 给患者降温，这将是SCA复苏的一大进步。