ASICs and increased ischemic brain injury in diabetic condition

描述（由申请人提供）：动物和人体研究表明，缺血性卒中急性期的糖尿病或高血糖症与临床结局恶化有关。尽管已经提出了包括氧化应激增加在内的许多可能性，但在高血糖背景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，我们假设钙渗透性酸敏感离子通道（ASIC）的激活增加在糖尿病患者缺血期间脑损伤增加中起重要作用：（1）酸中毒是脑缺血的常见特征，特别是在糖尿病患者中。（2）酸中毒以pH依赖性方式激活脑神经元中的Ca 2+可渗透ASIC;（3）这些通道的激活在与脑缺血相关的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，对本申请至关重要的是，我们的初步研究表明，（如在经历局部缺血的受影响脑区域中所预期的）进一步增强这些通道的活性并且如果葡萄糖剥夺之前是高血糖症则增强的程度更显著，一种与糖尿病患者有关的病症。使用电生理学、荧光成像、ASIC敲除小鼠、体外和体内缺血和糖尿病模型的组合，我们的目标是严格测试Ca 2+可渗透ASIC在高血糖大鼠/小鼠对缺血性脑损伤的敏感性增加中的作用。从这些研究中获得的结果将为糖尿病和高血糖患者相关的神经元损伤增加提供新的机制，并最终有助于为这些卒中患者开发新的神经保护策略，这是目前缺乏的。

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.