Remote Ischemic Conditioning:Translating Endogenous Neuroprotection in Embolic St

描述（由申请人提供）：远程缺血预处理（RIPerC），即在致死性器官缺血期间和再灌注前使用亚致死性“远程”短暂缺血，已被提议作为缺血事件的新型疗法。已发现其在心肌梗死（MI）动物模型中有效，并且在MI的随机临床试验中也有效。最近也有关于RIPerC在具有机械闭塞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可能是一种有前途的治疗急性卒中的方法。因此，重要的是在生理性中风模型中测试和优化RIPerC治疗的有效性，并在两种性别的老年动物中测试是否使用IV-tPA。为了更好地“模拟”人类中风，我们开发了一种生理和临床相关的部分人源化的中风小鼠栓塞模型，并在老年雄性和雌性动物中进行了验证。我们的长期目标是开发一种便宜、安全的中风治疗方法，可用于所有类型的临床环境，并与IV-tPA联合使用。栓塞MCAO凝块模型中的初步数据显示，RIPerC单独减少年轻雄性小鼠的缺血性损伤，并增强中风后“晚期”tPA治疗的益处。我们的具体目标是：目标1：优化RIPerC单独使用和与远程缺血后处理（RIPostC）联合使用的有效方案，以增强IV-tPA治疗在年轻男性中的获益，并研究短期和长期功能结局。我们将优化最有效的RIPerC治疗方案（有/无RIPostC）。我们将使用年轻雄性动物确定最佳方案，我们将在目标2中对两种性别的老年动物进行试验。我们将测量脑血流量、功能结局、梗死面积和出血性转化。目标二：确定优化的远程预处理方案与IV-tPA联合使用的有效性，以研究老年雄性和生殖衰老雌性小鼠（约18月龄）的长期获益。在这个目标中，我们将调查每日死亡率和长期的功能结果的电池的行为测试。我们还将在第28天测量损伤大小。这些结果将为UO 1提交奠定基础，在更大的动物模型（猪）和兔栓塞凝块模型中具有进一步的疗效里程碑，并最终提交急性缺血性卒中早期临床试验的IDE。

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.