The Next Step: Regadenoson mitigates ischemia reperfusion injury and is renal protective in a 48 hour porcine model of resuscitative ECMO

下一步：Regadenoson 可减轻缺血再灌注损伤，并在 48 小时复苏性 ECMO 猪模型中具有肾脏保护作用

• 批准号: 10611429
• 负责人: Mark Roeser
• 金额: $ 16.55万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-09 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10611429
• 关键词: ADORA2A gene; Acute; Acute Kidney Tubular Necrosis; Adenosine; Agonist; Animal Model; Anti-Inflammatory Agents; Apoptosis; Area; Attenuated; Blood Vessels; Brain; CD3 Antigens; CD4 Positive T Lymphocytes; Cardiac; Career Choice; Catheters; Cause of Death; Cell Adhesion; Cells; Chest; Circulation; Clinical; Clinical Trials; Data; Detection; Development; Extracorporeal Membrane Oxygenation; FDA approved; Family suidae; Fatal Outcome; Fluorescein; Funding; Future; Grant; HMGB1 gene; Heart; Heart Arrest; Heart Injuries; Hepatic; Hippocampus; Histology; Hour; IV Fluid; Inflammation; Inflammatory; Injury; Injury to Kidney; Intercellular Adhesion Molecules; Intercellular adhesion molecule 1; Interleukin-10; Interleukin-4; Intestinal permeability; Intestines; Investigational New Drug Application; Ischemia; Isothiocyanates; K-Series Research Career Programs; Kidney; Liver; Masks; Measures; Membrane; Mentors; Mitochondrial DNA; Modeling; Molecular; Monitor; Myocardial; Natural regeneration; Neutrophil Activation; Organ; Output; Pathologic; Pathologist; Pathway interactions; Patients; Pattern; Permeability; Plasma; Prognosis; Proteins; Reactive Oxygen Species; Recovery; Refractory; Renal function; Reperfusion Injury; Reperfusion Therapy; Reporting; Research; Research Personnel; Resuscitation; Role; Serum; Survivors; Syndrome; System; TNF gene; TdT-Mediated dUTP Nick End Labeling Assay; Technology; Therapeutic; Tight Junctions; Tissues; Training; Translational Research; Tubular formation; Urine; Ventilator; Weaning; Western Blotting; Work; active method; attenuation; body system; cell free DNA; central nervous system injury; claudin 3; clinical translation; cytokine; experience; experimental study; fluorescein isothiocyanate dextran; frontal lobe; heart function; improved; indexing; interstitial; intestinal barrier; intestinal injury; light microscopy; liver injury; mechanical circulatory support; monocyte; neutrophil; occludin; organ injury; porcine model; receptor; restoration; skills; targeted treatment; tubular necrosis

This is an application for a career development award to provide the PI with training in translation research. Building on ischemia reperfusion injury research performed by his mentors, the PI will use his acute resuscitative porcine animal model and extend it to 48 hours to look at end organ injury/recovery. This will further separate his career path from his mentors and set him up for funding for a clinical trial. Cardiac arrest is one of the leading causes of death worldwide, and resuscitative extracorporeal membrane oxygenation (ECMO) has emerged as a therapeutic option for refractory cardiac arrest, which was reported in almost 4,000 patients worldwide in 2017. The focus of the current proposal is to build upon our successful 6- hour ECMO porcine model and extend it to 48 hours to fully assess organ injury and recovery. We are also using an FDA-approved A2AR agonist (Regadenoson) to maximize the clinical translatability and to bring this therapy to patients. This project represents a paradigm shift in the management of ECMO from a supportive role to active treatment of the underlying problem, IRI organ injury. Resuscitatve ECMO is the most extreme example of IRI, but this treatment will be applied to all future resuscitative mechanical circulatory support. Specific Aim 1A will show that Regadenoson attenuates systemic organ injury in a 48-model of resuscitative ECMO. We will look at several markers of CNS, cardiac, liver, kidney, and intestinal injury as well as cytokine levels. CD3+ and CD4+ T cells, monocytes and neutrophils, and several damage-associated molecular pattern (DAMP) molecules will be assessed including HMGB1, cell-free DNA fragments and mitochondrial DNA. Aim 1B will show improved organ function in the groups treated with Regadenoson. Cardiac function will be assessed by cardiac index measured by a Swan-Ganz catheter and echocardiographs (ECHO) as well as the amount of inotropic support, IV fluid requirement and ECMO flows. Urine output will be collected and measured, and intestinal permeability will be determined via fluorescein isothiocyanate (FITC) gavage. Specific Aim2 will show how Regadenoson attenuates organ injury and improves organ function through several mechanisms including attenuation of neutrophil activation with reduced apoptosis, decreased membrane barrier permeability and fewer reactive oxygen species in the liver, kidney, intestine, heart, and brain. This mechanistic aim will provide additional scientific support for the use of A2AR activation to attenuate IRI in multiple organ systems. Dr Laubach is a senior researcher who has studied IRI for more than two decades and will serve as a mentor for this aim of the grant. Specific Aim3 will propose a clinical trial to determine if Regadenoson provides a durable clinical improvement in multiple organ systems in patients with post-arrest reperfusion with resuscitative ECMO. I will use the skills obtained from my course work and mentoring from Drs. Lau and Kron to submit a FDA investigational new drug application during the fourth year of this project, so I can submit an R01 proposal for clinical trial funding during the final year.

这是一份职业发展奖申请，旨在为 PI 提供翻译研究培训。 在导师进行的缺血再灌注损伤研究的基础上，PI 将利用他的急性 复苏猪动物模型并将其延长至 48 小时以观察终末器官损伤/恢复。这将 进一步将他的职业道路与导师分开，并为他获得临床试验的资金。 心脏骤停是全世界死亡的主要原因之一，复苏体外膜 氧合（ECMO）已成为难治性心脏骤停的一种治疗选择，据报道 2017 年全球有近 4,000 名患者。当前提案的重点是在我们成功的 6- 小时 ECMO 猪模型，并将其延长至 48 小时，以全面评估器官损伤和恢复情况。我们也是 使用 FDA 批准的 A2AR 激动剂 (Regadenoson) 最大限度地提高临床可转化性并带来这一效果 对患者进行治疗。该项目代表了 ECMO 管理模式从支持性的转变 积极治疗根本问题（IRI 器官损伤）的作用。复苏ECMO是最极端的 IRI 的例子，但这种治疗将应用于未来所有的复苏机械循环支持。 具体目标 1A 将表明 Regadenoson 可减轻 48 复苏模型中的全身器官损伤 ECMO。我们将研究中枢神经系统、心脏、肝脏、肾脏和肠道损伤的几种标志物以及细胞因子 水平。 CD3+ 和 CD4+ T 细胞、单核细胞和中性粒细胞以及几种损伤相关分子模式 (DAMP) 分子将被评估，包括 HMGB1、无细胞 DNA 片段和线粒体 DNA。目的 图1B将显示用Regadenoson治疗的组中器官功能的改善。心脏功能将会 通过 Swan-Ganz 导管和超声心动图 (ECHO) 测量的心脏指数以及 正性肌力支持量、IV 液体需求和 ECMO 流量。将收集尿液排出量并 测量，并通过异硫氰酸荧光素 (FITC) 灌胃测定肠道通透性。具体的 Aim2 将展示 Regadenoson 如何通过多种方式减轻器官损伤并改善器官功能 机制包括中性粒细胞活化减弱、细胞凋亡减少、细胞膜减少 屏障通透性和肝、肾、肠、心脏和脑中的活性氧较少。这 机制目标将为使用 A2AR 激活来减弱 IRI 提供额外的科学支持 多器官系统。 Laubach 博士是一位高级研究员，研究 IRI 已有二十多年， 将担任该赠款目标的导师。具体目标3将提出一项临床试验，以确定是否 Regadenoson 为逮捕后患者的多器官系统提供持久的临床改善 使用复苏性 ECMO 进行再灌注。我将利用从我的课程作业和指导中获得的技能 博士。 Lau 和 Kron 将在该项目的第四年向 FDA 提交研究性新药申请， 这样我就可以在最后一年提交 R01 临床试验资助提案。