ASICs and increased ischemic brain injury in diabetic condition

ASIC 与糖尿病患者缺血性脑损伤的增加

• 批准号: 8274760
• 负责人: ZHIGANG XIONG
• 金额: $ 30.95万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8274760
• 关键词: ASIC channel; Acidosis; Acute; Affect; Animals; Biotinylation; Brain; Brain Injuries; Brain Ischemia; Brain region; Cell Culture Techniques; Cerebral Ischemia; Chemosensitization; Clinical; Data; Development; Diabetes Mellitus; Diabetic mouse; Drops; Electrophysiology (science); Glucose; Glutamates; Human; Hyperglycemia; Hypoglycemia; Image; In Vitro; Injection of therapeutic agent; Injury; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Knockout Mice; Link; Long-Term Effects; Mediating; Modeling; Molecular; Mus; Neuronal Injury; Neurons; Outcome; Oxidative Stress; Oxygen; Patients; Phase; Play; Property; Protons; Rattus; Role; Streptozocin; Stroke; Surface; Testing; Western Blotting; base; deprivation; desensitization; diabetic; diabetic patient; extracellular; in vivo; in vivo Model; knockout gene; neuroprotection; non-diabetic; novel

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.

描述（由申请人提供）：动物和人类研究在缺血性中风的急性期与临床结局的恶化联系在一起。尽管已经提出了许多可能性，包括增加氧化应激，但在高血糖症情况下，这种恶化的细胞和分子机制仍然难以捉摸。我们假设增加Ca2+渗透性酸感应离子通道（ASIC）的激活在缺血期间与糖尿病患者相关的增加脑损伤起着重要作用，这是基于以下参数和初步数据的重要作用：（1）酸中毒是酸中毒是脑部缺血的常见特征，尤其是在糖尿病患者中。在非糖尿病状态下缺血后，脑pH降至6.5，但在糖尿病或高血糖状况下可能降至6.0以下。 （2）酸中毒以pH依赖性方式激活脑神经元中的Ca2+渗透性ASIC； （3）这些通道的激活在与脑缺血有关的酸中毒介导的独立神经元损伤中起着重要作用。 （4）此外，对于这种应用的核心，我们的初步研究表明，剥夺葡萄糖（正受到缺血的受影响的大脑区域的预期）进一步增强了这些通道的活性，并且如果葡萄糖剥夺之前，增强程度更大，如果葡萄糖剥夺的程度更为巨大。我们的目标结合了电生理学，荧光成像，ASIC敲除小鼠，体外和体内缺血和糖尿病模型，我们的目标是严格测试Ca2+可渗透ASIC在高血糖大鼠/小鼠高血糖大鼠敏感性中的作用。从这些研究中获得的结果将为与糖尿病和高血糖患者相关的神经元损伤增加的新机制，并最终有助于这些中风患者的新型神经保护策略的发展，目前缺乏这些中风患者。