ASICs and increased ischemic brain injury in diabetic condition

描述(由申请人提供)：动物和人类研究已将缺血性中风急性期的糖尿病或高血糖与临床结果恶化联系起来。虽然已经提出了包括增加氧化应激在内的许多可能性，但在高血糖环境下这种恶化的细胞和分子机制仍然难以捉摸。基于以下论点和初步数据，我们推测钙离子通透性酸敏感离子通道(ASICs)的激活在糖尿病患者脑缺血相关损伤增加中起重要作用：(1)酸中毒是脑缺血的共同特征，尤其是糖尿病患者。(2)酸中毒以pH依赖的方式激活脑神经元内钙离子通透性ASICs；(3)这些通道的激活在酸中毒介导的谷氨酸非依赖性神经元损伤中起重要作用；(4)此外，也是这一应用的核心，我们的初步研究表明，剥夺葡萄糖(正如所预期的那样，在经历缺血的受影响的脑区)进一步增强了这些通道的活性，并且如果剥夺葡萄糖之前伴有高血糖，则增强程度更显著，这是一种与糖尿病患者相关的情况。我们的目标是结合电生理学、荧光成像、ASIC基因敲除小鼠、体外和体内缺血和糖尿病模型，严格测试钙离子通透性ASIC在高血糖大鼠/小鼠对缺血性脑损伤敏感性增加中的作用。这些研究的结果将为糖尿病和高血糖患者增加神经元损伤提供新的机制，并最终将有助于为这些中风患者开发新的神经保护策略，这是目前所缺乏的。

DESCRIPTION (provided by applicant): Animal and human studies have linked diabetes or hyperglycemia in the acute phase of ischemic stroke to worsening of clinical outcomes. Although a host of possibilities including increased oxidative stress have been suggested, the cellular and molecular mechanisms for this worsening in the setting of hyperglycemia remain elusive. We hypothesize that increased activation of Ca2+permeable acid sensing ion channels (ASICs) plays an important role in increased brain injury associated with diabetic patients during ischemia based on the following arguments and preliminary data: (1) Acidosis is a common feature of brain ischemia particularly in diabetic patients. Brain pH drops to 6.5 following ischemia in non-diabetic conditions but can drop to below 6.0 in diabetic or hyperglycemic conditions; (2) Acidosis activates Ca2+permeable ASICs in brain neurons in a pH dependent manner; (3) Activation of these channels plays an important role in acidosis-mediated glutamate independent neuronal injury associated with brain ischemia; (4) In addition, and central to this application, our preliminary studies demonstrate that deprivation of glucose (as expected in the affected brain region undergoing ischemia) further potentiates the activity of these channels and that the degree of potentiation is more dramatic if glucose deprivation is preceded by hyperglycemia, a condition pertinent to diabetic patients. Using a combination of electrophysiology, fluorescent imaging, ASIC knockout mice, in vitro and in vivo ischemia and diabetes models, our objective is to rigorously test the role of Ca2+ permeable ASICs in the increased sensitivity of hyperglycemic rats/mice to ischemic brain injury. Results achieved from these studies will provide a new mechanism for increased neuronal injury associated with diabetic and hyperglycemic patients, and will ultimately contribute to the development of novel neuroprotective strategies for these stroke patients, which is currently lacking.