Elevated Zinc in Ischemia and reperfusion

缺血和再灌注时锌含量升高

• 批准号: 7074230
• 负责人: YANG V LI
• 金额: $ 22.05万
• 依托单位: OHIO UNIVERSITY ATHENS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7074230
• 关键词: apoptosis; calcium flux; cell death; cerebral ischemia /hypoxia; fluorescence microscopy; fluorescent dye /probe; hippocampus; intermolecular interaction; ion channel blocker; laboratory rat; neural degeneration; neurophysiology; neurotoxicology; neurotoxins; nitric oxide; pathologic process; reperfusion; tissue /cell culture; zinc

DESCRIPTION (provided by applicant): Stroke and heart attack kill nearly one million people each year in the U.S. alone. There are currently 5.3 million Americans living with a disability caused by brain injury, the result of an either external physical force or internal causes such as anoxia, stroke/ischemic insult, Alzheimer disease, or epilepsy. These neuropathologies often cause an impairment of cognitive, emotional, and/or physiological functioning in the CMS. It has been known for several years that cerebral ischemic episodes, such as those triggered by stroke or by heart attack, are accompanied by massive release of glutamate and Ca2+ overload. However, experimental treatments targeting Ca2+ homeostasis have not been very successful in reducing the volume or severity of neuronal damage. Accumulating evidence suggests that Zinc (Zn2+) is involved in excitotoxic neuronal death after head trauma, epilepsy, cerebral ischemia and reperfusion. Recently, we demonstrated that ischemia as simulated by oxygen and glucose deprivation caused an increase in Zn2+ concentration in global hippocampal slices. Subsequent reperfusion with standard medium resulted in a further increase in Zn2+ levels. The objective is to understand the role of Zn2+ in neuronal damage by determining the relationships of elevated Zn2+ with Ca2+, and by clarifying the role of Zn2+ in ischemic neuronal injury. The Overall Hypothesis of this proposal is that there is an increase in intracellular Zn2+ during OGD and reperfusion. The Zn2+ elevation could contribute to conventional Ca2+ signals or a Ca2+ overload. Therefore, this Zn2+ accumulation could be the precursor for neuronal damage under these conditions and could be the rightful target of therapeutic development of ischemic stroke. The Specific aims of this project are: (1) To identify Zn2+ signals in conventional Ca2+ signaling during transient ischemia as simulated by oxygen and glucose deprivation (OGD) and reperfusion. (2) To determine the interaction of Zn2+ and Ca2+ signaling during transient ischemia. (3) To determine whether elevated Zn2+ is vital to neuronal cell death in transient ischemia. Understanding the nature of Zn2+ accumulation and preventing the development and consequences of high extracellular and intracellular Zn2+ in the brains of patients who have suffered a stroke or heart attack could permit rapid therapeutic intervention to save vulnerable neurons.

描述（由申请人提供）：仅在美国，每年就有近100万人死于中风和心脏病发作。目前，有530万美国人生活在由脑损伤引起的残疾中，这种脑损伤要么是由外部物理力量造成的，要么是由缺氧、中风/缺血性损伤、阿尔茨海默病或癫痫等内部原因造成的。这些神经病变通常会导致CMS患者的认知、情绪和/或生理功能受损。多年来人们已经知道，脑缺血发作，如中风或心脏病发作，伴随着大量释放谷氨酸和Ca2+超载。然而，针对Ca2+稳态的实验治疗在减少神经元损伤的体积或严重程度方面并不是很成功。越来越多的证据表明，锌（Zn2+）参与脑外伤、癫痫、脑缺血再灌注后的兴奋性毒性神经元死亡。最近，我们证明了缺氧和葡萄糖剥夺模拟的缺血导致海马整体切片中Zn2+浓度增加。随后用标准介质再灌注导致Zn2+水平进一步升高。目的是通过确定Zn2+升高与Ca2+的关系，并通过阐明Zn2+在缺血性神经元损伤中的作用，了解Zn2+在神经元损伤中的作用。本提议的总体假设是在OGD和再灌注期间细胞内Zn2+增加。Zn2+升高可能导致常规Ca2+信号或Ca2+过载。因此，这种Zn2+积累可能是这些条件下神经元损伤的前兆，可能是缺血性中风治疗发展的正确目标。本项目的具体目的是：(1)在氧和葡萄糖剥夺（OGD）和再灌注模拟的短暂缺血过程中，识别常规Ca2+信号中的Zn2+信号。(2)确定短暂性缺血时Zn2+和Ca2+信号的相互作用。(3)探讨Zn2+升高是否对短暂性缺血神经元细胞死亡至关重要。了解Zn2+积累的本质，防止中风或心脏病患者大脑中细胞外和细胞内高Zn2+的发展和后果，可以实现快速治疗干预，以挽救脆弱的神经元。