Trophic Factor Signaling and Motor Neuron Death

描述（由申请人提供）：本提案侧重于受体酪氨酸激酶在使运动神经元易受神经退行性损伤中的作用。TrkB被其配体脑源性神经营养因子激活。几个独立的实验室表明，体外阻断TrkB激活可以保护神经元免受特定的损伤。尽管这些观察是异端，但我们在体外和特定的体内环境中看到了同样的现象。在具体目标#1中，我们将通过将突变SOD小鼠置于TrkBF616A背景下来研究这一过程的时间方面。TrkBF616A可被口服活性血脑屏障渗透剂1NMPP1特异性拮抗。第二种酪氨酸激酶受体是胰岛素/胰岛素样生长因子受体（IGF-R）。在模式生物中（最近在小鼠中），当IGF-R的活性降低时，保守的应激抵抗途径被激活。FOXO3a转录因子在蠕虫和苍蝇的这一过程中起着关键作用，但其在脊椎动物中的功能尚不清楚。在特定目标#2中，我们将确定FOXO3a的缺失是改善还是加剧了突变SOD小鼠运动神经元疾病。在我们对FOXO3a的研究过程中，我们发现了一种海洋海绵化合物（Psammaplysene a， PA），它可以促进转录因子的核定位，并且在体外和体内神经变性模型中具有广泛的神经保护作用。虽然有强有力的证据表明这种化合物通过FOXO3a起作用，但确切的分子靶点尚不清楚。在具体的目标#3中，将采用几种方法来寻找PA作用的靶点和途径。总的来说，这项工作试图找到新的疾病调节剂，减缓运动神经元疾病的进展。如果成功，新的治疗靶点将会出现。

DESCRIPTION (provided by applicant): This proposal focuses on the role of receptor tyrosine kinases in rendering motor neurons susceptible to neurodegenerative insults. TrkB is activated by its ligand, brain-derived neurotrophic factor. Several independent laboratories show that blocking TrkB activation in vitro can protect neurons from specific insults. Despite the heresy of these observations, we have seen the same phenomenon in vitro and in a specific in vivo circumstance. In specific aim #1 we will investigate the temporal aspect of this process by putting the mutant SOD mouse on a TrkBF616A background. TrkBF616A can be specifically antagonized by the orally active, blood brain barrier permeable agent, 1NMPP1. A second receptor tyrosine kinase of interest is the Insulin/Insulin-like growth factor receptor (IGF-R). In model organisms (and recently in mice) a conserved stress resistance pathway is evoked when the activity of the IGF-R is reduced. The FOXO3a transcription factor plays a key role in this process in worms and flies, but its function in vertebrates is unknown. In specific aim #2, we will determine if loss of FOXO3a ameliorates or exacerbates the mutant SOD mouse motor neuron disease. In the course of our investigations of FOXO3a, we found a marine sponge compound (Psammaplysene A, PA) that promotes nuclear localization of the transcription factor and is broadly neuroprotective in in vitro and in vivo models of neurodegeneration. While the evidence is strong that the compound works through FOXO3a, the precise molecular target is not known. In specific aim #3, several approaches will be employed to find the target and pathway through which PA acts. Overall this work attempts to find new disease modifiers that slow the progression of motor neuron disease. If successful, new therapeutic targets will emerge.