TRANSYNAPTIC CORTICAL APOPTOSIS--MECHANISMS & THERAPIES

描述：（来自申请人摘要的逐字记录） 皮质皮质通路的退化是 病理学的传播系统退化中的细胞死亡， 大脑皮层包括阿尔茨海默病我们建议，这种类型的 变性可能代表致病性的适当和现实的靶点， 这些疾病中的事件。在目前的建议中，我们专注于一个非常可靠的 我们最近在跨突触皮质变性的体内模型中， 发达国家，即，梨状核锥体神经元凋亡 大脑皮层的变化。我们调查 眼球切开术后的特定细胞/分子事件， 去传入神经元远端树突的兴奋性毒性型改变， 影响这些神经元的NOS/NO信号传导;以及细胞周期和死亡基因 如Cyclin D1和Bax。确认解剖/表达数据 在实验中，我们使用了一些药理学干预措施，包括： 影响细胞凋亡但不影响兴奋性毒性的蛋白质合成抑制剂; 靶向谷氨酸合成、释放和结合的小分子 兴奋性毒性，并在这样做，消除凋亡皮层细胞的改善 死亡; NOS抑制剂/NO清除剂;细胞周期蛋白依赖性激酶抑制剂， 阻断细胞周期蛋白信号传导;和半胱天冬酶抑制剂。我们也用遗传基因 防止凋亡性神经元死亡的优点（例如，nNOS空值，bax空值， ICE-显性阴性Tgs）。我们希望这些精心控制的 研究将揭示关键的中间机制的皮质 并将建议临床上有利的方法来治疗这些 紊乱

DESCRIPTION: (Verbatim from the Applicant's Abstract) Transsynaptic degeneration of corticocortical pathways is a central mechanism for the propagation of pathology an cell death in systems degenertions involving the cerebral cortex, including Alzheimer's disease. We propose that this type of degeneration may represent an appropriate and realistic target of pathogenic events in these disorders. In the present proposal, we focus on a very reliable in vivo model of transsynaptic cortical degeneration that we have recently developed, i.e., the apoptotic death of pyramidal neurons in the piriform cortex after their disconnection from the olfactory bulb. We investigate specific cellular/molecular events subsequent to bulbotomy such as excitotoxic-type alterations of distal dendrites of deafferented neurons, NOS/No signaling impacting on these neurons; and cell cycle and death genes such as Cyclin D1 and bax. To confirm data from anatomical/expression experiments, we use a number of pharmacological interventions, including: protein synthesis inhibitors that influence apoptosis but not excitotoxicity; small molecules that target glutamate synthesis, release and binding to block excitotoxicity and, in so doing, ameliorate of abolish apoptotic cortical cell death; NOS inhibitors/NO scavengers; cyclin-dependent kinase inhibitors to block cyclin signaling; and caspase inhibitors. We also use mice with genetic advantages that prevent apoptotic neuronal death (e.g., nNOS nulls, bax nulls, ICE-dominant negative Tgs). We expect that these carefully controlled investigations will shed light on critical intermediate mechanisms of cortical degenerations and will suggest clinically advantageous methods to treat these disorders.