Trophic Factor Signaling and Motor Neuron Death

描述（由申请人提供）：该提案重点关注受体酪氨酸激酶在使运动神经元对神经退行性损伤敏感中的作用。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，在体外阻断TrkB激活可以保护神经元免受特异性损伤。尽管这些观察结果是异端邪说，但我们已经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TrkBF 616 A背景下来研究该过程的时间方面。TrkBF 616 A可被口服活性的血脑屏障渗透剂1 NMPP 1特异性拮抗。感兴趣的第二种受体酪氨酸激酶是胰岛素/胰岛素样生长因子受体（IGF-R）。在模型生物中（以及最近在小鼠中），当IGF-R的活性降低时，会诱发保守的应激抗性途径。FOXO 3a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。在具体目标#2中，我们将确定FOXO 3a的缺失是否改善或加重突变型SOD小鼠运动神经元疾病。在我们对FOXO 3a的研究过程中，我们发现了一种海绵化合物（Psammaperidae A，PA），它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该化合物通过FOXO 3a起作用，但确切的分子靶点尚不清楚。在具体目标#3中，将采用几种方法来找到PA作用的靶标和途径。总的来说，这项工作试图找到新的疾病修饰剂，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。 公共卫生相关性：目前尚不清楚为什么特定的神经元群体容易受到神经退行性刺激的毒性作用。在这个提议中，我们将研究两个信号通路在使运动神经元容易受到与Lou Gehrig病相关的损伤中所起的作用。此外，我们还鉴定了一种具有显著神经保护活性的小分子。在这个提议中，我们将确定这种分子的分子靶点和它运作的信号通路。

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. PUBLIC HEALTH RELEVANCE: It is not known why specific neuronal populations are vulnerable to the toxic effects of neurodegenerative stimuli. In this proposal we will examine the role played by two signaling pathways in rendering motor neurons susceptible to insults relevant to Lou Gehrig's disease. In addition, we have identified a small molecule with remarkable neuroprotective activity. In this proposal we will determine the molecular target of this molecule and the signaling pathway through which it operates.