Trophic Factor Signaling and Motor Neuron Death

肌萎缩侧索硬化症(ALS)的中心病理事件是选择性运动变性 神经元。虽然大多数病例(-90%)是零星的，但家族性病例是由于各种基因突变所致。 不同的基因如SOD1和p150粘合在一起。谷氨酸受体过度激活(兴奋性毒性) 是一个早期的触发事件。兴奋性损伤或突变基因表达导致运动神经元死亡 可以在使用分离的啮齿动物胚胎脊髓组织的细胞培养中进行研究。我们之前的试管婴儿 研究表明，兴奋性运动神经元死亡只有在脑源性神经营养因子 (BDNF)通过TrkB的信号是完整的。磷脂酰肌醇3‘激酶(PiS’K)信号通路被激活 TrkB和PiS‘K信号通路是BDNF诱导的兴奋性中毒性马达死亡的充要条件 神经元。抑制Trk激活的药物操作也可以保护运动神经元免受 突变体sod1和p150的毒性效应。这可以使用专有的 K252a(由Cephalon制药公司制造)或通过抑制腺苷A2a受体的激活。在……里面 具体目标#1我们将检查以下细胞内信号级联的变化 这些代理的管理。突变体SOD1与p150gled和Trk之间的潜在相互作用 信令事件也将被研究。在特定的目标#2，我们将研究在体内的药效学 这些药物对Trk的激活和信号转导有影响。这是我们希望进行的未来研究的前奏 在肌萎缩侧索硬化症动物模型中检查这些药物的疗效。在具体目标#3中，我们将研究信令 激活的PiS‘K(两个丝氨酸茶氨酸激酶(PDK1，Akt)和小单体)下游级联 RhoA和Arf家族的GTP)，以了解哪一种需要唤起电机的兴奋性毒性敏感性 神经元。这将定义运动神经元对毒性的易感性细胞内信号通路。 相关性：拟议的工作试图将基础科学观察转化为新的治疗方法 肌萎缩侧索硬化。针对肌萎缩侧索硬化症的新药靶点的开发可以为其他、更多的 普遍存在的神经退行性疾病。

The central pathologic event in Amyotrophic Lateral Sclerosis (ALS) is the selective degeneration of motor neurons. While most cases (-90%) are sporadic, the familial cases are due to mutations in a variety of different genes such as SOD1 and p150glued. Excessive activation of glutamate receptors (excitotoxicity) is an early triggering event. The death of motor neurons from excitoxic insult or mutant gene expression can be studied in cell culture using dissociated rodent embryonic spinal cord tissue. Our previous in vitro work demonstrates that excitotoxic motor neuron death only occurs if Brain-derived neuronotrophic factor (BDNF) signaling via TrkB is intact. The phosphatidylinositol 3' kinase (PIS'K) signaling cascade is activated by TrkB and PIS'K signaling is necessary and sufficient for BDNF-induced excitotoxic death of motor neuron. Pharmacological manipulations that inhibit Trk activation can also protect motor neurons from the toxic effects of mutant SOD1 and p150glued. This can be accomplished using proprietary derivatives of K252a (made by Cephalon Pharmaceuticals) or by inhibiting the activation of adenosine A2A receptors. In specific aim #1 we will examine the alterations in intracellular signaling cascades that follow from administration of these agents. The potential interplay between mutant SOD1 and p150glued and Trk signaling events will also be studied. In specific aim #2, we will study the in vivo pharmacodynamics of these agents on Trk activation and signaling. This is a prelude to future studies in which we hope to examine the efficacy of these agents in animal models of ALS. In specific aim #3 we will study the signaling cascades downstream of activated PIS'K (two serine-theonine kinases (PDK1, Akt) and small monomeric GTP'ases of the RhoA and Arf families) to see which is needed to evoke excitotoxic sensitivity of motor neurons. This will define susceptiblity-to-toxicity intracellular signaling pathways in motor neurons. Relevance: The proposed work attempts to translate basic science observations into new treatments for ALS. The development of new drug targets for ALS could guide the way for novel therapies for other, more prevalent, neuro-degenerative disorders.