TPA MEDIATED NEURODEGENERATION & MICROGLIAL ACTIVATION

描述：(改编自申请者摘要)：神经元死亡 在哺乳动物大脑中的位置不仅是病理条件的结果 例如癫痫、阿尔茨海默氏症和脑缺血，但在 正常的发育过程。成人大脑的一个区域，其中 选择性神经元变性和死亡的情况特别好。 记录在案的是海马体，空间学习的结构。和 记忆是统一的。这种神经元死亡，可以被诱导 在实验上，被认为代表了一种夸张的过程形式 通常与可塑性和突触重组有关。 最近的工作已经确定了一种介导神经元退化的基因。这 组织纤溶酶原激活物(TPA)基因编码一种丝氨酸蛋白酶 在海马体中表达，转录活性非常高 迅速在之后 兴奋性毒素引起的癫痫发作或电刺激。TPA的这种增加 表达之后是海马神经元的变性和死亡 细胞。在缺乏功能性tPA基因的突变小鼠中，海马体 神经细胞对这种兴奋性毒素诱导的变性/死亡具有抵抗力。 TPA也被怀疑与学习过程中的正常功能有关， 记忆和一般突触可塑性事件。 尽管tPA是由大脑某些区域的神经元基本合成的 而周围神经系统、海马区tPA在损伤后迅速升高 似乎主要来源于小胶质细胞。此外，小胶质细胞 在导致神经元死亡的事件中，细胞通常会被“激活”； 然而，tPA缺陷小鼠的小胶质细胞仅表现为有限。 激活。综上所述，(和其他)观察结果表明 神经元退化是协调的多细胞过程的结果。我们的 目前对tPA作用的理解提出了一些直接和 可立即解决的问题：需要哪些蜂窝交互 会引发神经元退化吗？什么信号调节tPA的合成和 分泌物？TPA基因产物的蛋白水解性表明 组织纤溶酶原激活剂介导神经元变性的途径；底物起什么作用 TPA采取行动了吗？在这个途径中还需要哪些基因？最后，如何 TPA能扩展我们对神经元分子基础的认识吗？ 变性和小胶质细胞激活？

DESCRIPTION: (Adapted from Applicant's Abstract): Neuronal death takes place in the mammalian brain not only as a result of pathological conditions such as epilepsy, Alzheimer's disease, and ischemia, but as well during the normal processes of development. One region of the adult brain in which selective neuronal degeneration and death have been particularly well documented is the hippocampus, the structure in which spatial learning. and memory are consolidated. This neuronal death, which can be induced experimentally, is thought to represent an exaggerated form of the processes normally involved in plasticity and synaptic reorganization. Recent work has identified a gene that mediates neuronal degeneration. This gene, tissue plasminogen activator (tPA), encodes a serine protease expressed in the hippocampus that becomes transcriptionally activated very rapidly after excitotoxin-induced seizure or electrical stimulation. This increase in tPA expression is followed by degeneration and death of the hippocampal neuronal cells. In mutant mice lacking a functional tPA gene, the hippocampal neuronal cells are resistant to such excitotoxin-induced degeneration/death. tPA is also suspected to be involved in normal functioning during learning, memory, and general synaptic plasticity events. Although tPA is synthesized basally by neurons in some regions of the brain and peripheral nervous system, the rapid rise in hippocampal tPA upon injury appears to derive primarily from microglial cells. In addition, microglial cells normally become "activated" during events that lead to neuronal death; however, microglial cells in tPA-deficient mice demonstrate only limited activation. Taken together, the (and other) observations suggest that neuronal degeneration results from a coordinated multicellular process. Our current understanding of tPA's role raises a number of direct and immediately addressable questions: What cellular interactions are required to elicit neuronal degeneration? What signals regulate tPA's synthesis and secretion? The proteolytic nature of the tPA gene product suggests a direct means by which tPA might mediate neuronal degeneration; what substrates does tPA act on? What other genes are required in the pathway? And finally, how can tPA be used to extend our knowledge of the molecular basis of neuronal degeneration and microglial activation?