Remote Ischemic Conditioning:Translating Endogenous Neuroprotection in Embolic St

描述(由申请人提供)：远程缺血预适应(RIPerC)，在致命性器官缺血期间和再灌注之前使用亚致死性“远程”短暂性缺血，已被提议作为一种治疗缺血事件的新方法。它在心肌梗死(MI)动物模型中被发现是有效的，在MI的随机临床试验中也是有效的。最近也有关于RIPerC在机械闭塞和再灌注的啮齿动物卒中模型中的疗效的报道。这些令人鼓舞的发现表明，RIPerC可能是治疗急性中风的一种有前途的治疗方法。因此，在生理性卒中模型中测试和优化RIPerC治疗的有效性以及在老年动物中使用和不使用IV-tPA是重要的。为了更好地“模拟”人类卒中，我们开发了一种生理和临床相关的部分人源化的卒中小鼠栓塞模型，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廉价、安全的中风疗法，可以在所有类型的临床环境中使用，并与静脉注射tPA联合使用。在栓塞性MCAO血栓模型中的初步数据显示，RIPerC单独减少了年轻雄性小鼠的缺血性损伤，并增强了中风后“晚期”tPA治疗的好处。我们的具体目标是：目标1：优化RIPerC单独和联合远程缺血后处理(RIPostC)的有效治疗方案，以加强IV-tPA治疗对年轻男性的益处，并观察其短期和长期功能结果。我们将优化使用/不使用RIPostC的最有效的RIPerC治疗方案。我们将使用年轻的雄性来确定我们将在目标2中在老年动物身上测试的最佳方案。我们将测量脑血流量、功能结果、脑梗塞面积和出血转化。目的：确定优化的远程调理方案与静脉注射tPA联合应用的有效性，以探讨其对老年雄性和雌性生殖衰老(~18月龄)小鼠的长期益处。在这个目标中，我们将通过一系列行为测试来调查每日死亡率和长期功能结果。我们还将在第28天测量受伤的大小。这些结果将为UO1的提交奠定基础，并在更大的动物模型(猪)和兔血栓模型中取得进一步的疗效里程碑，并最终提交IDE用于急性缺血性中风的早期临床试验。

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.