Growth factor regulation of neuronal metabolism

胚胎和成体神经元的存活和生长受神经营养因子如神经生长因子（NGF）和胰岛素及胰岛素样生长因子（IGFs）调节。神经营养因子控制一系列信号转导途径，通过在转录、转录后和翻译后水平调节基因表达来调节神经元的表型。神经元要进行这样一系列的催化和稳态操作，就必须有稳定的代谢物和能量供应，然而，神经元调节自身代谢和能量产生的过程却知之甚少。我们将检验神经营养因子通过直接控制代谢物水平和ATP合成的信号转导途径增强神经元生长和存活的假设。我们在成人感觉神经元中的初步研究表明，神经营养因子，如NGF和胰岛素，通过激活磷酸肌醇3-激酶途径（PI 3-kinase）增强线粒体功能和提高ATP水平。最近的研究结果表明，PI 3-激酶下游的多功能酶Akt在指导神经营养因子依赖性信号控制神经元代谢中起着重要作用。我们未来工作的目标将是充分识别神经元生长因子所利用的途径，主要集中在PI 3-激酶/Akt和Raf-1/MEK/ERK途径，以调节中枢和外周神经系统（CNS和PNS）的胚胎和成年神经元中线粒体生物能量学的全谱。这些目标是新颖的，因为（i）将研究将神经营养因子信号传导与线粒体生物能量学的维持联系起来的信号转导途径，（ii）将用纯化的酶处理分离的线粒体并评估对线粒体功能的影响，（iii）将在神经元中解决神经营养因子依赖性代谢物加工的机制，以及（iv）将对来自成人的神经元进行研究，以及胚胎、CNS和PNS组织。

The survival and growth of embryonic and adult neurons is regulated by neurotrophic factors, such as nerve growth factor (NGF) and insulin and insulin-like growth factors (IGFs). Neurotrophic factors control an array of signal transduction pathways that modulate the phenotype of neurons through adjustment of gene expression at the transcriptional, post-transcriptional and post-translational levels. For the neuron to perform such a range of catalytic and homeostatic operations there must be a constant supply of metabolites and energy, however, the processes whereby neurons regulate their own metabolism and energy production are poorly understood. We will test the hypothesis that neurotrophic factors enhance neuronal growth and survival through signal transduction pathways that directly control metabolite levels and ATP synthesis. Our preliminary studies in adult sensory neurons indicate that neurotrophic factors, such as NGF and insulin, enhance the mitochondrial function and raise ATP levels through activation of the phosphoinositide 3-kinase pathway (PI 3-kinase). Recent results indicate a central role for the multi-functional enzyme Akt, downstream of PI 3-kinase, in directing neurotrophic factor-dependent signals controlling neuronal metabolism. The objective of our future work will be to fully identify the pathways utilized by neuronal growth factors, focusing mainly on the PI 3-kinase/Akt and Raf-1/MEK/ERK pathways, to modulate the full spectrum of mitochondrial bioenergetics in embryonic and adult neurons of the central and peripheral nervous systems (CNS and PNS). The aims are novel because (i) the signal transduction pathway(s) linking neurotrophic factor signaling to maintenance of mitochondrial bioenergetics will be investigated, (ii) isolated mitochondria will be treated with purifed enzymes and effects on mitochondrial function assessed, (iii) the mechanism of neurotrophic factor-dependent metabolite processing will be addressed in neurons and (iv) studies will be performed on neurons from adult, as well as embryonic, CNS and PNS tissues.