Neuroglobin: cell metabolism and neuroprotection

描述（由申请人提供）：脑红蛋白（Ngb）是最新发现的球蛋白之一，其优先定位于脊椎动物脑中的神经元，对广泛的神经障碍具有明确的神经保护作用。然而，Ngb的神经保护作用的机制仍然不确定。神经元的特点是高代谢活动和执行快节奏的能量需求过程。此外，神经元的营养储存较差，特别容易受到缺血性损伤。Ngb在新生儿脑中的表达最高，这与新生儿脑中脂肪生成的高峰一致。 大脑和神经组织中存在糖原。有趣的是，新生儿脑中较高的Ngb表达与长期公认的新生儿缺血耐受相关。我们已经在神经元细胞系中产生了稳定的Ngb过表达，并证明Ngb过表达显著抑制AMPK信号传导并增加细胞糖原和脂质含量。结果表明，Ngb过表达小鼠皮层神经元AMPK活性降低，糖原合成酶活性增强。这些数据提供了Ngb可能通过AMPK信号调节神经元代谢的第一个证据。即使在无氧条件下，增加神经元的糖原和脂肪生成对ATP的产生也有明显的优势。我们的初步研究进一步表明，AMPK激活减弱了Ngb过表达的神经保护作用。考虑到AMPK信号在细胞代谢中的良好功能，Ngb对氧的高亲和力，以及Ngb和AMPK主要在CNS的神经元中表达，Ngb可能与AMPK信号相互作用并在神经元代谢中发挥关键作用是合理的。我们的中心假设是Ngb过表达通过抑制AMPK途径增加营养储存能力，从而提供对缺血性卒中的神经保护作用。我们将讨论以下两个具体目标来检验我们的中心假设。1.确定Ngb过表达在神经元代谢中的作用和生理条件下的潜在机制。2.确定AMPK介导的合成代谢作用参与Ngb过表达对缺血性卒中的神经保护作用。这些拟议的研究预计将产生重要的积极影响，因为它们可能会确定新的治疗靶点，最终导致发现缺血性卒中的治疗方法。

DESCRIPTION (provided by applicant): Neuroglobin (Ngb) is one of the latest discovered globins that preferentially localize to neurons in vertebrate brain with a well-defined neuroprotective effect against a wide range of neurological disorders. However, the mechanism underlying the neuroprotective action of Ngb is still uncertain. Neurons are characterized by high metabolic activity and execute fast-paced energy-demanding processes. Moreover, neurons have poor nutrient storage and are particularly vulnerable to ischemic insult. Ngb expression is at the highest in neonatal brains which is coincident with the peak of lipogenesis in the brain and with the presence of glycogen in neural tissue. Interestingly, the higher Ngb expression in neonatal brain is associated with the long recognized ischemic tolerance in neonates. We have generated stable Ngb overexpression in a neuronal cell line and demonstrated that Ngb overexpression significantly inhibits AMPK signaling and increases cellular glycogen and lipid contents. Consistently, AMPK inhibition and glycogen synthase activation were found in cortical neurons of Ngb overexpression mice. These data provided the first evidence that Ngb might regulate neuron metabolism through AMPK signaling. Enhancing glycogenesis and lipogenesis in neuron could have distinct advantage for ATP production even under anaerobic condition. Our preliminary study further demonstrated that AMPK activation diminished the neuroprotection of Ngb overexpression. Given the well-established function of AMPK signaling in cellular metabolism, the high affinity of Ngb to oxygen, and that both Ngb and AMPK predominately express in neurons at CNS, it is plausible that Ngb might interact with AMPK signaling and play a critical role in neuron metabolism. Our central hypothesis is that Ngb overexpression increases nutrient storage capacity via inhibition of AMPK pathway and, thus, provides neuroprotective action against ischemic stroke. We will address the following two specific aims to test our central hypothesis. 1. Determine the role of Ngb overexpression in neuron metabolism and underlying mechanisms in physiological condition. 2. Determine the involvement of AMPK-mediated anabolic action in the neuroprotective effect of Ngb overexpression against ischemic stroke. The proposed studies are expected to have an important positive impact because they may identify novel therapeutic target that ultimately lead to the discovery of treatment for ischemic stroke.