Peptide-Mediated Enhancement of Akt During Resuscitation and Reperfusion

复苏和再灌注过程中肽介导的 Akt 增强

• 批准号: 10843727
• 负责人: Cody Nicholas Justice
• 金额: $ 5.27万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2025-12-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10843727
• 关键词: 6-Phosphofructo-2-kinase; Adult; Affect; Biological Assay; Blood; Blood specimen; Brain; Cannulas; Cardiac; Cardiopulmonary Resuscitation; Cells; Cerebrovascular Circulation; Cerebrum; Chicago; Development; Dichloroacetate; Emergency Situation; Ensure; Family suidae; Glucose; Goals; Heart; Heart Arrest; Hour; Illinois; In Vitro; Ischemia; Leukocytes; Magnetic Resonance; Magnetic Resonance Imaging; Mammals; Mechanics; Mediating; Metabolic; Metabolic dysfunction; Metabolism; Methods; Modeling; Mus; Myocardial Ischemia; Myocardial Stunning; NMR Spectroscopy; Neurologic; Neurologic Deficit; Neurological outcome; Organ; Outcome; Oxygen; PH Domain; PTEN gene; Pathologic; Patients; Penetration; Peptides; Persons; Pharmaceutical Preparations; Phosphorylation; Physicians; Population; Principal Investigator; Protein Dephosphorylation; Protein phosphatase; Public Health; Rattus; Recovery; Recovery of Function; Reperfusion Injury; Reperfusion Therapy; Resolution; Resuscitation; Role; SLC2A1 gene; Sampling; Scientist; Specificity; Survivors; Techniques; Testing; Tissues; Toxic effect; Training; Translating; United States; Universities; Vanadium; cardioprotection; disability; experience; fatty acid oxidation; glucose metabolism; glucose uptake; heart function; improved; improved outcome; in vivo; inhibitor; insight; intravenous administration; leucine-rich repeat protein; metabolic rate; mouse model; neurological recovery; neuroprotection; novel; out-of-hospital cardiac arrest; oxidation; peripheral blood; pharmacologic; porcine model; pre-clinical; prevent; pyruvate dehydrogenase; resuscitative care; skills; small molecule; survival outcome; tat Protein; tool; underserved area

PROJECT SUMMARY/ABSTRACT Out-of-hospital cardiac arrest is a significant public health burden, affecting over 350,000 people annually in the United States. Survival remains less than 12% and long-term neurological deficit is common in survivors. Currently no drugs exist to reverse myocardial stunning or improve long-term survival with good neurological outcome, which highlights an urgent and unmet need in resuscitation. Pharmacological stimulation of cardiac glucose oxidation represents a potential key strategy for enhancing recovery and reversing a pathological increase in fatty acid oxidation which occurs after ischemia, although agents such as dichloroacetate are limited by toxicity. A novel cell-penetrating peptide, TAT-PHLPP9c, was developed which rapidly gains access to tissues and selectively inhibits PHLPP1, thereby enhancing activation of Akt. In a mouse model of cardiac arrest, intravenous administration of TAT-PHLPP9c during CPR improves recovery of cerebral blood flow and enhances activation of both Akt and pyruvate dehydrogenase in the heart and brain. In swine, administration of TAT- PHLPP9c during mechanical CPR significantly improves 24-hour survival. Agents such as TAT-PHLPP9c that quickly gain access to tissues to improve survival would represent a significant advancement in resuscitation. Targeting metabolic dysfunction with TAT-PHLPP9c may decrease the circuit flow rate needed for successful eCPR, which will allow for narrow cannulas to be used and may lead to wider availability of eCPR. Using high resolution magnetic resonance methods, this project will investigate the mechanisms underlying TAT-PHLPP9c cardioprotection and neuroprotection. The following hypotheses will be tested: 1) TAT-PHLPP9c directly targets the heart and enhances functional recovery from ischemia; 2) TAT-PHLPP9c decreases fatty acid oxidation in the post-ischemic heart; 3) TAT-PHLPP9c treatment during low flow eCPR improves cardiac arrest survival, neurological recovery, cerebral blood flow, and cerebral metabolism; 4) TAT-PHLPP9c reduces the circuit flow rate required for successful eCPR; and 5) TAT-PHLPP9c-mediated Akt activation in peripheral blood leukocytes reflects Akt activation in tissues from vital organs. These hypotheses will be tested using a Langendorff model of rat heart ischemia/reperfusion injury, a swine model of eCPR, and a mouse model of cardiac arrest. It is our ultimate goal to translate these findings to emergency resuscitative care in order to save lives and minimize long- term neurological disability after cardiac arrest. A comprehensive training plan will develop the principal investigator’s skills as a physician-scientist under the guidance of the sponsor (Terry L. Vanden Hoek, MD, University of Illinois at Chicago) and co-sponsor (Henry R. Halperin, MD, MA, Johns Hopkins University).

项目总结/摘要 院外心脏骤停是一个重大的公共卫生负担，在美国每年影响超过35万人。 美国的存活率仍然低于12%，长期神经功能缺损在幸存者中很常见。 目前还没有药物可以逆转心肌顿抑或改善长期生存， 结果，这突出了复苏的迫切和未满足的需求。心脏药理刺激 葡萄糖氧化代表了一种潜在的关键策略， 局部缺血后发生的脂肪酸氧化增加，尽管诸如二氯乙酸盐的试剂是有限的 毒性。开发了一种新的细胞穿透肽TAT-PHLPP9c，其快速进入组织 并选择性抑制PHLPP 1，从而增强Akt的活化。在心脏骤停的小鼠模型中， 在CPR期间静脉内施用TAT-PHLPP9c改善了脑血流量的恢复，并增强了 心脏和大脑中Akt和丙酮酸脱氢酶的激活。在猪中，施用TAT- PHLPP9c在机械CPR期间显著改善24小时存活率。试剂如TAT-PHLPP9c， 快速进入组织以提高存活率将代表复苏的重大进步。 用TAT-PHLPP9c靶向代谢功能障碍可以降低成功治疗所需的回路流速。 eCPR，这将允许使用狭窄的套管，并可能导致eCPR的更广泛的可用性。使用高 分辨率磁共振方法，本项目将调查TAT-PHLPP9c的机制 心脏保护和神经保护。将检验以下假设：1）TAT-PHLPP9c直接靶向 TAT-PHLPP9c可降低心肌缺血后的脂肪酸氧化， 缺血后心脏; 3）低流量eCPR期间的TAT-PHLPP9c治疗改善心脏骤停存活， 神经功能恢复、脑血流量和脑代谢; 4）TAT-PHLPP9c减少回路流量 5）TAT-PHLPP9c介导的外周血白细胞中Akt活化 反映了重要器官组织中Akt的激活。这些假设将使用Langendorff模型进行检验 大鼠心脏缺血/再灌注损伤模型、猪eCPR模型和小鼠心脏骤停模型。是我们 最终目标是将这些发现转化为紧急复苏护理，以挽救生命，并最大限度地减少长期 心脏骤停后的长期神经功能障碍一个全面的培训计划将培养校长 研究者在申办者的指导下作为一名医生-科学家的技能（Terry L. Vanden Hoek，医学博士， 伊利诺伊大学芝加哥分校）和共同赞助人（亨利R。Halperin，MD，MA，Johns霍普金斯大学）。