CYTOSKELETAL PROCESSING AND SUBLETHAL BRAIN INJURY

细胞骨架加工和亚致死脑损伤

• 批准号: 6273914
• 负责人: JON S MORROW
• 金额: $ 24.54万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6273914
• 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.

早产对长期发育有很大风险 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胺类药物异常敏感 突触水平引起的致死性缺氧和缺血性损伤 在此期间发生的重塑和凋亡修剪。 然而，突触可塑性背后的因素或调节 人们对细胞凋亡的反应知之甚少，几乎不可能 对新生儿进行研究。基于一个新的实体 有证据表明，神经元的幽灵蛋白细胞骨架 有助于突触的组织、形状和反应，以及 也可能在介导细胞对细胞凋亡的反应中发挥作用 诱导信号。与这一角色密切相关的似乎是其 对钙离子激活的中性蛋白水解酶的敏感性在于u-calain和 白介素化蛋白(ICE)家族成员CPP32。在……里面 为了研究钙蛋白水解酶和CPP32裂解在体内的作用。 有关大脑发育过程的血影蛋白，及其 对伤害的反应，转基因小鼠将被制备成表达 大脑中的幽灵蛋白已经被突变，以减少其 对钙蛋白酶和/或CPP32裂解的敏感性。这些老鼠将会是 分析大脑成熟受损的证据，电生理 功能、突触密度、细胞凋亡停滞等变化。这个 这些小鼠对亚致死性缺氧和缺血应激的反应 也要接受评估。总而言之，这些研究承诺将产生我们的 首次真正深入了解幽灵蛋白骨架在突触中的作用 生态学和神经细胞凋亡，并可能提供一个独特的体内模型 检查围产期脑损伤的后果。