CYTOSKELETAL PROCESSING AND SUBLETHAL BRAIN INJURY

细胞骨架加工和亚致死脑损伤

• 批准号: 6455821
• 负责人: JON S MORROW
• 金额: $ 29.31万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6455821
• 关键词: apoptosis; biological signal transduction; brain injury; calpain; cerebral cortex; cerebral ischemia /hypoxia; cytoskeleton; developmental neurobiology; epitope mapping; gene expression; genetically modified animals; glia; glutamates; hippocampus; laboratory mouse; mutant; neural plasticity; neurons; neurotoxicology; phenotype; proteolysis; site directed mutagenesis; spectrin; tissue /cell culture; transfection

Premature birth poses a substantial risk for long-term developmental and cognitive impairment, even in the absence of overt brain injury. We hypothesize that the neonatal brain is unusually sensitive to sub- lethal hypoxic and ischemic injury because of the level of synaptic remodeling and apoptotic pruning that occurs during this period. However, the factors that underlie synaptic plasticity or that mediate the apoptotic response are poorly understood and almost impossible to study in neonatal children. Based on a new substantial body of evidence it has become clear that the neuronal spectrin cytoskeleton contributes to synaptic organization, shape, and responsiveness, and may also play a role in mediating the cells response to apoptosis inducing signals. Closely associated with this role appears to be its sensitivity to Ca++ activated neutral proteases lie u-calpain and to the interleukin converting protease (ICE) family member CPP32. In order to study the in vivo role of calpain and CPP32 cleavage of spectrin on processes involved with brain development, and its response to injury, transgenic mice will be prepared that express brain spectrin that has been mutated so as to reduce its susceptibility to calpain and /or CPP32 cleavage. these mice will be analyzed for evidence of impaired brain maturation, electrophysiologic function, synaptic density, apoptotic arrest, and other changes. The response of these mice to sub lethal hypoxic and ischemic stress will also be evaluated. Collectively, these studies promise to yield our first real insights into the role of the spectrin skeleton in synapse ecology and neuronal apoptosis, and may provide a unique in vivo model for examining the consequences of perinatal brain damage.

早产对长期发育造成重大风险 和认知障碍，即使没有明显的脑损伤。 我们假设新生儿的大脑对亚- 致死性缺氧缺血性损伤，因为突触水平 在此期间发生的重塑和凋亡修剪。 然而，突触可塑性的基础或介导的因素， 对凋亡反应了解很少， 研究新生儿。 基于一个新的实质性机构， 有证据表明，神经元血影蛋白细胞骨架 有助于突触的组织、形状和反应， 也可能在介导细胞对凋亡的反应中起作用 诱导信号。 与这一角色密切相关的似乎是其 对Ca++激活的中性蛋白酶Lie u-钙蛋白酶和对 白细胞介素转化蛋白酶（ICE）家族成员CPP 32。 在 为了研究钙蛋白酶和CPP 32切割的体内作用， 血影蛋白对大脑发育过程的影响， 对于损伤的反应，将制备表达 脑血影蛋白已被突变，以减少其 对钙蛋白酶和/或CPP 32切割的易感性。 这些老鼠将会 分析了大脑成熟受损、电生理 功能、突触密度、凋亡停滞和其他变化。 的 这些小鼠对亚致死性缺氧和缺血应激的反应将 也被评价。 总的来说，这些研究有望产生我们的 第一次真实的深入了解血影蛋白骨架在突触中的作用 生态和神经元凋亡，并可能提供一个独特的体内模型， 用于检查围产期脑损伤的后果。