Humanin as a novel cardioprotective and angiogenic factor

描述（由申请人提供）：Humanin是一种24个氨基酸的肽，其在阿尔茨海默氏病中的神经保护作用最为人所知。在我们的初步研究中，我们表明，humanin可以保护缺血前15分钟用humanin预处理的小鼠免受缺血/再灌注损伤。这些心脏保护作用背后的机制尚不清楚，但我们的第一个假设是，humanin的作用是由G蛋白偶联受体（GPCR）和PLC的激活介导的。这种激活反过来又导致两种途径的激活，一种涉及PKC和ATP敏感性钾通道，另一种涉及PI 3 K和Akt。我们的第二个假设是humanin是一种新的血管生成因子，其血管生成作用是通过PI 3 K/Akt通路介导的。我们的具体目标是：1.2）评估GPCR/PLC <$/PKC/mitoKATP通道通路在humanin预处理效应中的作用; 1.3）检查PI 3 K/Akt存活通路在humanin抗凋亡作用中的作用; 2.1）评估PI 3 K/Akt通路在humanin的血管生成作用中的作用; 2.2）鉴定humanin在小鼠心脏来源的内皮细胞中诱导的血管生成基因; 2.3）检查humanin在梗死心肌中的新血管形成中的作用。在临床上，作为一种潜在的治疗剂，humanin具有许多吸引人的特性。例如，作为内源性肽，它应该具有最小的副作用。此外，humanin具有延迟的心脏保护作用，这对于需要心脏骤停的患者来说是非常有益的。最后，Humanin的血管生成作用可以促进受损心肌中的新血管形成，改善心脏功能。这项研究中产生的信息最终将有助于探索使用humanin作为心脏病新疗法的可能性。每年有40万人死于缺血性心脏病;因此，寻找新的心脏保护剂至关重要。我们的研究旨在提供对于人蛋白作为治疗剂的开发至关重要的信息。Humanin具有三个主要特性，使其成为一种优秀的治疗剂。首先，它是一种天然存在的激素，应该具有最小的副作用。第二，humanin具有延迟的心脏保护作用，这对于需要心脏骤停的患者（例如冠状动脉搭桥术）是有用的。最后，humanin具有促进受损心肌中新血管形成的潜力。

DESCRIPTION (provided by applicant): Humanin is a 24 amino-acid peptide that is best known for its neuroprotective effects in Alzheimer's disease. In our pilot studies, we showed that humanin can protect against ischemia/reperfusion injury in mice pretreated with humanin 15 minutes before ischemia. The mechanism behind these cardioprotective effects is not clear, but our first hypothesis is that the effects of humanin are mediated by the activation of a G- protein-coupled receptor (GPCR) and PLC¿. This activation, in turn, leads to the activation of two pathways, one involving PKC and ATP-sensitive potassium channels, and the other involving PI3K and Akt. Our second hypothesis is that humanin is novel angiogenic factor and its angiogenic effect is mediated by PI3K/Akt pathway. Our specific aims are: 1.1) To determine the effective dose and optimal time of humanin administration that confers myocardial protection; 1.2) To assess the role of the GPCR/PLC¿/PKC/mitoKATP channel pathway in the preconditioning effect of humanin; 1.3) To examine the role of the PI3K/Akt survival pathway in the anti-apoptotic action of humanin; 2.1) To assess the role of the PI3K/Akt pathway in the angiogenic effect of humanin; 2.2) To identify the angiogenic genes induced by humanin in mouse heart- derived endothelial cells; 2.3) To examine the effect of humanin in neovascularization in infarcted myocardium. Clinically, humanin has a number of attractive properties as a potential therapeutic agent. For example, as an endogenous peptide, it should have minimal side effects. In addition, humanin has a delayed cardioprotective effect, which would be of great benefit for patients undergoing procedures in which cardiac arrest is necessary. Finally, the angiogenic effect of humanin may promote neovascularization in the damaged myocardium, improving the function of the heart. The information generated in this study will ultimately help explore the possibility of using humanin as a novel treatment for heart disease. Pr 400,000 people die every year from ischemic heart disease; as such, the search for new cardioprotective agents is of utmost importance. Our study is designed to provide information that will be important for the development of humanin as a therapeutic agent. Humanin has three main properties that would make it an excellent therapeutic agent. First, it is a naturally occurring hormone that should have minimal side effects. Second, humanin has a delayed cardioprotective effect, which would be useful for patients in which cardiac arrest is needed (e.g. coronary bypass). Finally, humanin has the potential to promote new blood vessel formation in damaged myocardium.