TRANSYNAPTIC CORTICAL APOPTOSIS--MECHANISMS & THERAPIES

描述：(逐字摘自申请者的摘要)跨突触 皮质通路的退化是脑出血的主要机制 病理学的传播一种系统退化中的细胞死亡，涉及 大脑皮层，包括阿尔茨海默病。我们建议这种类型的 退行性变可能代表了致病的适当和现实的靶点 这些失调症中的事件。在本提案中，我们将重点放在一个非常可靠的 我们最近建立的跨突触皮质变性的活体模型 发育，即梨状体内锥体神经元的凋亡性死亡 在他们与嗅球断开连接后，大脑皮层。我们在调查 球部切开术后的特定细胞/分子事件，如 去传入神经元远端树突的兴奋性毒性改变， 一氧化氮合酶/一氧化氮信号对这些神经元的影响；以及细胞周期和死亡基因 如Cyclin D1和Bax。确认来自解剖/表达的数据 在实验中，我们使用了许多药理学干预措施，包括： 影响细胞凋亡但不具有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以阻断 兴奋性毒性，并在这样做的过程中，改善取消凋亡的皮质细胞 死亡；一氧化氮合酶抑制剂/一氧化氮清除剂；细胞周期蛋白依赖性激酶抑制剂 阻断细胞周期蛋白信号；和caspase抑制剂。我们也用基因突变的小鼠 防止神经元凋亡性死亡的优点(例如，nNOS null，Bax nulls， 以冰为主的负TGS)。我们预计这些经过精心控制的 研究将有助于阐明皮质激素的关键中间机制 并将建议临床上有利的方法来治疗这些 精神错乱。

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.