Remote Ischemic Conditioning:Translating Endogenous Neuroprotection in Embolic St

远程缺血调理：栓塞治疗中的内源性神经保护

基本信息

批准号：
8634820
负责人：
DAVID C. HESS
金额：
$ 18.56万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-15 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8634820
关键词：
Acute Address Age Alteplase Animal Model Animals Arteries Behavior Therapy Blood Pressure Blood coagulation Blood flow Cerebral hemisphere hemorrhage Cerebrovascular Circulation Clinical Clinical Data Clinical Trials Coagulation Process Communication Communities Critiques Data Devices Economic Inflation Effectiveness Elderly Erythropoietin Event FDA approved Failure Family suidae Female Future Goals Hospitals Hour Human Individual Industry Infarction Injury Intravenous Ischemia Ischemic Stroke Leg Measures Mechanics Modeling Monitor Mus Myocardial Infarction Neurological outcome Organ Oryctolagus cuniculus Outcome Patients Pharmaceutical Preparations Phase Physiological Protocols documentation Randomized Clinical Trials Recommendation Regimen Reperfusion Therapy Reporting Retrieval Risk Rodent Safety Stroke Symptoms Testing Therapeutic Translating Work acute stroke aged behavior test cerebral artery clinically relevant conditioning cost design functional outcomes improved innovation instrument male mortality neuroprotection novel pre-clinical preclinical study public health relevance research clinical testing research study restoration senescence sex stroke therapy success

项目摘要

DESCRIPTION (provided by applicant): Remote ischemic per-conditioning (RIPerC), the use of sub-lethal "remote" transient ischemia during lethal organ ischemia and prior to reperfusion, has been proposed as a novel therapy for ischemic events. It has been found effective in animal models of myocardial infarction (MI) and was also effective in a randomized clinical trial in MI. There are also recent reports of the efficacy of RIPerC in rodent stroke models with mechanical occlusion and reperfusion. These encouraging findings suggest that RIPerC may be a promising treatment for acute stroke. Therefore, it is important to test and optimize the effectiveness of RIPerC therapy in a physiological stroke model and to test with and without IV-tPA in aged animals of both sexes. To better "model" human stroke, we developed a physiological and clinically relevant partially- humanized mouse embolic model of stroke and have validated it in aged male and female animals. Our long term goal is to develop an inexpensive, safe therapy for stroke that could be used in all types of clinical settings, and in combination with IV-tPA. Ou preliminary data in an embolic MCAO clot model shows that RIPerC reduces the ischemic injury alone in young male mice and potentiated the benefits of "late" tPA therapy after stroke. Our specific aims are: AIM 1: Optimize the effective regimen of RIPerC alone and in combination with remote ischemic post-conditioning (RIPostC) to potentiate the benefits of IV-tPA treatment in young males and to investigate the short and long term functional outcome. We will optimize the most effective regimen of RIPerC therapy with/without RIPostC. We will use young males to determine the optimal regimen that we will test in aged animals of both sexes in Aim 2. We will measure cerebral blood flow, functional outcomes, infarct size and hemorrhagic transformation. Aim 2: Determine the effectiveness of the optimized remote conditioning regimen in combination with IV-tPA to investigate the long term benefits in aged male and reproductively senescent female mice (~18 months old). In this aim, we will investigate daily mortality and long term functional outcome on a battery of behavioral tests. We will also measure the injury size at day 28. These results will lay the groundwork for a UO1 submission with further milestones of efficacy in a larger animal model (pig) and in a rabbit embolic clot model and the eventual submission of an IDE for an early phase clinical trial in acute ischemic stroke.

描述（由申请人提供）：远程缺血性每条件（RIPERC），在致死器官缺血期间使用亚致死性“远程”短暂性缺血，并且在再灌注之前，已被提议作为缺血事件的新疗法。它在心肌梗死（MI）的动物模型中被发现有效，并且在MI的一项随机临床试验中也有效。最近还有关于RIPERC在具有机械遮挡和再灌注的啮齿动物中风模型中的功效的报道。这些令人鼓舞的发现表明，RIPERC可能是急性中风的有前途的治疗方法。因此，重要的是要在生理中风模型中测试和优化RIPERC疗法的有效性，并在两性的老年动物中测试和没有IV-TPA。为了更好地“模型”人类中风，我们开发了一种生理和临床相关的部分人性化小鼠栓塞模型，并在老年男性和雌性动物中验证了它。我们的长期目标是开发一种廉价，安全的中风治疗，该治疗可用于所有类型的临床环境，并与IV-TPA结合使用。 OU在栓塞MCAO凝块模型中的初步数据表明，RIPERC可减少年轻雄性小鼠的缺血性损伤，并在中风后增强“晚期” TPA治疗的益处。我们的具体目的是：目标1：单独优化RIPERC的有效方案，并结合远程缺血后条件（RIPOSTC），以增强年轻男性IV-TPA治疗的益处，并研究短期和长期功能性结果。我们将使用/不使用RipostC优化RIPERC疗法的最有效方案。我们将使用年轻的男性来确定AIM 2中两性的老年动物测试的最佳方案。我们将测量脑血流，功能结果，梗塞大小和出血转化。目标2：确定优化的远程调节方案与IV-TPA结合使用的有效性，以研究老年男性和生殖性衰老雌性小鼠的长期益处（约18个月大）。在此目标中，我们将在一系列行为测试中调查每日死亡率和长期功能结果。我们还将测量第28天的损伤大小。这些结果将为UO1提交的基础奠定基础，并在较大的动物模型（PIG）和兔栓塞凝块模型中进一步的疗效里程碑，以及最终在急性缺血性中风的早期临床试验中提交IDE。