ANESTHETICS AND STRESS PROTEINS IN BRAIN CELL INJURY

描述：（改编自申请人摘要）脑缺血是 是这个国家的第三大死因， 围手术期并发症 作为细胞和分子的理解 缺血性脑损伤的病理生理学出现，新的治疗方法 可能性正在被发现。 内源性应激蛋白的应用 保护大脑的方法已经研究了一段时间， 候选人策略 在上一个资助期间，研究人员 能够证明单独的hsp 70和加热一样有效， 预处理保护脑细胞免受随后的缺血， 侮辱。 他们现在将通过三种方式寻求这种治疗的可能性。 首先，通过在转基因小鼠中进行研究以确定 增加hsp 70在体内的表达;第二，通过追求基因治疗， 体外使用hsp 70过表达的星形胶质细胞，第三，通过测定 另一种应激蛋白提供的保护范围， 保护免受氧化损伤，HSP 27。 1)局灶性脑缺血 在hsp 70转基因小鼠、纯合子转基因小鼠、杂合子转基因小鼠上进行 和非转基因同窝仔。 受伤的程度将由 磁共振成像（MRI）和组织学，梗死体积 将被计算。 2)如果找到了保护机制， 通过确定每种基因型的凋亡细胞的数量， 看看在转基因小鼠中是否检测到更少的凋亡细胞。 3)的 Hsp 70过量产生的星形胶质细胞的神经元保护机制将是 作为基因治疗的一个模型。 4)保护机制将 通过测定受保护的培养物中的谷氨酸水平来寻求， 与对照组相比， 5)保护的程度 将在过表达hsp 70的培养物中比较抗神经元损伤 星形胶质细胞或神经元或两种细胞类型。 6)热休克蛋白27的过度表达， 另一种应激蛋白，将被测试其提供脑细胞的能力， 保护免受三种不同的侮辱。 已知这种应激蛋白 稳定细胞骨架，并可能证明有益的设置 发生细胞骨架破坏的脑缺血。 知识 从这个项目中获得的直接影响， 缺血性中风在外科和内科患者中均存在。

DESCRIPTION: (Adapted from the applicant's abstract) Cerebral ischemia is the third leading cause of death in this country and is a feared perioperative complication. As cellular and molecular understanding of the pathophysiology of ischemic brain injury emerges, new treatment possibilities are being discovered. The use of endogenous stress proteins to protect the brain has been under study for some time and is a promising candidate strategy. In their previous funding period, the investigators were able to demonstrate that hsp70 alone was as effective as a heat pretreatment in protecting brain cells from subsequent ischemia like insults. They will now pursue this treatment possibility in three ways. First, by carrying out studies in transgenic mice to determine the effect of increased hsp70 expression in vivo; second, by pursuing gene therapy in vitro using hsp70 over expressing astrocytes, and third, by determining the range of protection provided by another stress protein important in protection from oxidative injury, hsp27. 1) Focal cerebral ischemia will be performed on hsp70 transgenic mice, homozygotic transgenic, heterozygotic and non-transgenic littermates. The extent of injury will be determined with magnetic resonance imaging (MRI) and histology, volumes of infarction will be calculated. 2) If protection is found, the mechanism will be pursued by determining the number of apoptotic cells for each genotype, to see if fewer apoptotic cells are detected in the transgenic mice. 3) The mechanism of neuronal protection by hsp70 overproducing astrocytes will be studied as one model for gene therapy. 4) The mechanism of protection will be sought by determining levels of glutamate in protected cultures deprived of oxygen and substrate compared to controls. 5) The extent of protection against neuronal injury will be compared in cultures over expressing hsp70 in astrocytes or neurons or both cell types. 6) Over expression of hsp27, another stress protein, will be tested for its ability to provide brain cell protection from three different insults. This stress protein is known to stabiize the cytoskeleton, and may prove beneficial in the setting of cerebral ischemia where cytoskeletal disruption occurs. The knowledge gained from this project has direct implications for the treatment of ischemic stroke in both surgical and medical patients.