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: 10402360
• 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/10402360
• 关键词: ADORA2A gene; Acute; Acute Kidney Tubular Necrosis; Adenosine; Agonist; Animal Model; Anti-Inflammatory Agents; Apoptosis; Area; Attenuated; Blood Circulation; Blood Vessels; Brain; CD3 Antigens; CD4 Positive T Lymphocytes; Cardiac; Career Choice; Catheters; Cause of Death; Cell Adhesion; Cell Adhesion Molecules; Cells; Chest; Clinical; Clinical Trials; Data; Detection; Development; Extracorporeal Membrane Oxygenation; FDA approved; Family suidae; Fatal Outcome; Fluorescein; Fluorescein-5-isothiocyanate; Funding; Future; Grant; HMGB1 gene; Heart; Heart Arrest; Heart Injuries; Hepatic; Hippocampus (Brain); Histology; Hour; IV Fluid; Inflammation; Inflammatory; Injury to Kidney; 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; 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; clinically translatable; cytokine; experience; experimental study; fluorescein isothiocyanate dextran; frontal lobe; heart function; improved; indexing; injury recovery; 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.

这是一个职业发展奖的申请，可为PI提供翻译研究的培训。 在他的导师进行的缺血再灌注损伤研究的基础上，PI将使用他的急性 复苏猪动物模型，并将其扩展到48小时，以查看最终器官损伤/恢复。这会 进一步将他的职业道路与导师分开，并为他准备临床试验的资金。 心脏骤停是全球死亡的主要原因之一，并且是复苏的体外膜 氧合（ECMO）已成为难治性心脏骤停的治疗选择，这在 2017年全球近4,000名患者。当前提案的重点是建立在我们成功的6-- 小时Ecmo猪模型并将其扩展到48小时，以完全评估器官损伤和恢复。我们也是 使用FDA批准的A2AR激动剂（Regadenoson）来最大化临床转换性并带来 对患者的治疗。该项目代表了ECMO管理的范式转变 主动治疗潜在问题，IRI器官损伤的作用。 Resuscitatve ECMO是最极端的 IRI的例子，但是这种处理将应用于所有未来的复苏机械循环支持。 具体目标1a将表明，雷加氏菌会减轻48型复苏的系统性器官损伤 ECMO。我们将查看CNS，心脏，肝脏，肾脏和肠损伤的几个标记以及细胞因子 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的分子模式 （潮湿）将评估分子，包括HMGB1，无细胞DNA片段和线粒体DNA。目的 1b将在用雷达尼森治疗的组中显示出改善的器官功能。心脏功能将是 通过Swan-Ganz导管和超声心动图（ECHO）测量的心脏指数评估 肌力支持，IV液的需求和ECMO流量的量。将收集尿量，并 测量的，肠道通透性将通过异硫氰酸荧光素（FITC）饲养确定。具体的 AIM2将显示Regadenoson如何减轻器官损伤并通过几种来改善器官功能 机制，包括减少凋亡，膜降低的中性粒细胞激活的衰减 肝脏，肾脏，肠，心脏和大脑中的屏障渗透性和较少的活性氧。这 机械目标将为使用A2AR激活来减轻IRI的额外科学支持 多器官系统。 Laubach博士是一位高级研究员，研究了IRI超过二十年， 将作为赠款目的的导师。特定的AIM3将提出临床试验，以确定是否是否 Regadenoson在逮捕后患者的多器官系统中提供了持久的临床改进 再灌注与复活的ECMO。我将使用我的课程工作中获得的技能，并从中获得指导 博士。 Lau和Kron在该项目的第四年内提交FDA调查新药申请， 因此，我可以在最后一年提交R01提案以进行临床试验资金。