Trophic Factor Signaling and Motor Neuron Death

肌萎缩侧索硬化（ALS）的中心病理事件是运动神经的选择性变性， 神经元虽然大多数病例（约90%）是散发性的，但家族性病例是由于多种基因突变引起的。 SOD 1和p150 glued等不同基因。谷氨酸受体过度激活（兴奋性毒性） 是一个早期触发事件。兴奋性毒性损伤或突变基因表达引起的运动神经元死亡 可以在使用解离的啮齿动物胚胎脊髓组织的细胞培养中进行研究。我们之前的体外试验 这项研究表明，只有当脑源性神经营养因子 通过TrkB的BDNF信号传导是完整的。磷脂酰肌醇3'激酶（PIS' K）信号级联被激活 通过TrkB和PISK信号传导是BDNF诱导的运动神经兴奋性毒性死亡的必要和充分条件 neuron.抑制Trk激活的药理学操作也可以保护运动神经元免受神经元损伤。 突变SOD 1和p150 glucose的毒性作用。这可以通过使用 K252 a（由Cephalon Pharmaceuticals制造）或通过抑制腺苷A2 A受体的活化。在 具体目标#1，我们将检查细胞内信号级联的改变， 管理这些代理商。突变SOD 1和p150 glued与Trk之间的潜在相互作用 还将研究信号事件。在具体目标#2中，我们将研究以下的体内药效学： 这些药物对Trk激活和信号传导的影响。这是未来研究的前奏，我们希望 检查这些药物在ALS动物模型中的疗效。在具体目标#3中，我们将研究信号传导 在活化的PISK（两种丝氨酸-苏氨酸激酶（PDK 1，Akt）和小单体激酶（PDK 1，Akt））下游的级联反应中， RhoA和Arf家族的GTP酶），以观察哪种酶是引起运动神经元兴奋毒性敏感性所需的。 神经元这将定义运动神经元中的易感性-毒性细胞内信号传导途径。 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， 人症ALS新药物靶点的开发可以为其他更多疾病的新疗法提供指导。 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.