CYTOSKELETAL PROCESSING AND SUBLETHAL BRAIN INJURY

细胞骨架加工和亚致死脑损伤

• 批准号: 6355620
• 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: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6355620
• 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.

早产给长期发展带来了重大风险 以及认知障碍，即使没有明显的脑损伤。 我们假设新生儿大脑对亚 致命的低氧和缺血性损伤，因为突触水平 在此期间发生的重塑和凋亡修剪。 但是，突触可塑性或介导的因素 凋亡的反应很少了解，几乎不可能 新生儿儿童的研究。 基于新的实质 证据很明显神经元细胞骨架 为突触组织，形状和响应能力做出贡献，并且 也可能在介导细胞对凋亡的反应中起作用 诱导信号。 与此角色紧密相关的似乎是 对Ca ++激活的中性蛋白酶的敏感性是U-钙蛋白酶的，对 白介素转化蛋白酶（ICE）家庭成员CPP32。 在 为了研究钙蛋白酶和cpp32裂解的体内作用 光谱涉及与大脑发育有关的过程及其 对损伤的反应，将准备转基因小鼠表达 已突变以减少其的脑谱 对钙蛋白酶和 /或CPP32裂解的敏感性。 这些老鼠会 分析了脑部成熟，电生理学障碍的证据 功能，突触密度，凋亡停滞和其他变化。 这 这些小鼠对亚致死性低氧和缺血压力的反应将 也可以评估。 这些研究共同承诺会产生我们的 首先对Spectrin骨架在突触中的作用的真正见解 生态学和神经元细胞凋亡，并可能提供独特的体内模型 检查围产期脑损伤的后果。