A2: PROJ 3: MECHANISMS OF ACIDOSIS ENHANCED ISCHEMIC BRAIN DAMAGE: DRUG

A2：项目 3：酸中毒增强缺血性脑损伤的机制：药物

• 批准号: 7336065
• 负责人: PING LI
• 金额: $ 8.87万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-17 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7336065
• 关键词: acidosis; astrocytes; brain; cell death; cerebral ischemia /hypoxia; cytokine; free radicals; glucose; hyperglycemia; inflammation; injury; interleukin 1; ischemia; mitochondria; morphology; neurons; proteins; reperfusion; role; stroke

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Diabetes exaggerates brain damage induced by cerebral ischemia. The underlying mechanisms for this important, clinically relevant phenomenon are poorly understood. The objective of this project is to identify the role of mitochondria and mitochondrial-initiated cell death pathways in hyperglycemic ischemia. The results obtained from past 5 years showed that that 1) both acidosis and high glucose contribute to the detrimental effects of hyperglycemia/diabetes on ischemic neurons; 2) cerebral ischemia in diabetics results in alteration of mitochondrial morphology. This includes severe mitochondrial swelling and release of mitochondrial matrix proteins at the early reperfusion phase after stroke; 3) diabetes induces expression of neuro-inflammatory molecules such as the pro-inflammatory cytokine interleukin-1 (IL-1) and intercellular adhesive molecule-1 (ICAM-1); 4) diabetic ischemia enhances production of free radicals, and activates the mitochondrion-mediated cell death pathway, resulting in nuclear fragmentation and cell death; 5) the detrimental effects of hyperglycemia on ischemic brain are not only to neurons but to astrocytes as well; 6) pharmacological agents that preserve mitochondria, scavenge free radicals or suppress neuro-inflammation protect the brain from ischemic injury in normoglycemic and/or hyperglycemic subjects.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。糖尿病会加剧脑缺血引起的脑损伤。对于这一重要的临床相关现象的潜在机制尚不清楚。该项目的目的是确定线粒体和线粒体引发的细胞死亡途径在高血糖缺血中的作用。过去5年的结果表明：1）酸中毒和高血糖都会导致高血糖/糖尿病对缺血神经元的有害影响； 2）糖尿病患者脑缺血导致线粒体形态改变。这包括中风后早期再灌注阶段线粒体严重肿胀和线粒体基质蛋白释放； 3）糖尿病诱导促炎细胞因子白细胞介素-1（IL-1）和细胞间粘附分子-1（ICAM-1）等神经炎症分子的表达； 4）糖尿病缺血会增强自由基的产生，并激活线粒体介导的细胞死亡途径，导致细胞核碎裂和细胞死亡； 5）高血糖对缺血脑的不利影响不仅对神经元而且对星形胶质细胞也有影响； 6) 保护线粒体、清除自由基或抑制神经炎症的药物可保护血糖正常和/或高血糖受试者的大脑免受缺血性损伤。