Neuroglobin: cell metabolism and neuroprotection

描述(申请人提供)：脑红蛋白(NGB)是最新发现的珠蛋白之一，优先定位于脊椎动物大脑中的神经元，对广泛的神经疾病具有明确的神经保护作用。然而，NGB神经保护作用的机制仍不确定。神经元具有高代谢活动的特点，并执行快节奏的能量需求过程。此外，神经元的营养储存能力很差，特别容易受到缺血性损伤的影响。NGB在新生儿脑中的表达最高，这与脂肪生成的高峰相一致。 大脑和神经组织中的糖原的存在。有趣的是，新生儿脑中NGB的高表达与新生儿长期公认的缺血耐受有关。我们已经在神经细胞系中产生了稳定的NGB过表达，并证明了NGB过表达显著抑制了AMPK信号转导，并增加了细胞糖原和脂质含量。在NGB过表达小鼠的大脑皮层神经元中，始终发现AMPK抑制和糖原合成酶激活。这些数据为NGB可能通过AMPK信号调节神经元代谢提供了第一个证据。即使在厌氧条件下，促进神经元的糖生成和脂肪生成对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过度表达的神经保护作用。鉴于AMPK信号在细胞代谢中的作用，NGB对氧的高度亲和力，以及NGB和AMPK主要在中枢神经系统的神经元中表达，NGB可能与AMPK信号相互作用，在神经元代谢中发挥关键作用。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，以检验我们的中心假设。1.在生理条件下，确定NGB过表达在神经元代谢中的作用及其可能机制。2.确定AMPK介导的合成代谢作用是否参与了NGB过表达对缺血性卒中的神经保护作用。这些拟议的研究有望产生重要的积极影响，因为它们可能确定新的治疗靶点，最终导致发现治疗缺血性中风的方法。

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.