IONIC & METABOLIC MECHANISMS IN HYPOXIC NEURONAL INJURY

在过去的10-15年里，我们的实验室一直在研究 在氧气限制条件下神经细胞的损伤或存活， 急性或慢性。特别是，我们最近的努力集中在 膜蛋白(如电压敏感型Na+和KATP)的作用 在分级低氧中发挥诱导神经元损伤或预防和 拖延时间。根据我们最近收集的初步数据和 作为中心赠款内部新合作的结果，我们有 公式化的假设旨在理解细胞和分子 离子通量和能量代谢作用的机制 缺氧和能量剥夺对神经元的损伤。我们的一般假设 神经细胞质膜钠依赖的交换器及其 在确定脆弱性方面，监管至关重要。 对神经元的损伤，不仅在急性时，而且在慢性氧气时 限制。以下是我们的具体假设：L)Na+内流 新皮质神经元是诱导缺氧性去极化和 分级限氧和恢复过程中的损伤； 减少Na+内流保护神经元，这种保护在一定程度上是 与高能代谢物的呈递有关；2)这种Na+内流 通过依赖于Na+的质膜交换器(如Na/H和 Na/Ca；3)慢性暴露动物的新皮质神经元 出生后对低氧更容易受到急性分级氧/血糖的影响 这是由于Na+增加所致 通过上调交换器的表达而流入，以及4)增加 暴露的新皮质神经元对氧/糖剥夺的易感性 是高能量代谢物更快耗尽的结果 Na+负荷增加。使用可操作的技术和方法 在我们的实验室，如电生理学、分子生物学 技术和磁共振波谱，我们将能够 回答所有4个假设。尽管我们意识到神经元 对低氧气的反应是非常复杂的，我们的长期目标是 干预这一系统以延长神经元存活或 防止神经细胞损伤。我们认为，目前的这些研究是 全面了解神经元反应和神经功能的关键步骤 适应短期和长期的压力。

In the last 10-15 years, our laboratory has been investigating mechanisms of nerve cell injury or survival during conditions of O2 limitation, acute or chronic. In particular, we have focused our recent efforts on the role that membrane proteins (e.g. voltage-sensitive Na+ and KATP) play during graded hypoxia in inducing neuronal damage or preventing and delaying it. Based on preliminary data that we have recently gathered and as a result of new collaborations within the Center Grant, we have formulated hypotheses aimed at understanding the cellular and molecular mechanisms underlying the role of ionic fluxes and energy metabolism in neuronal injury during O2 and energy deprivation. Our general hypothesis is that the neuronal plasma membrane Na-dependent exchangers and their regulation are of paramount importance in determining the vulnerability to neuronal injury not only during acute but also during chronic O2 limitation. The following are our specific hypotheses: l) Na+ influx into neocortical neurons is critical for inducing hypoxic depolarization and injury during graded O2 glucose limitation and during recovery; decreasing Na+ influx protects neurons and this protection is, in part, related to presentation of high energy metabolites; 2) this Na+ influx is mediated via Na+-dependent plasma membrane exchangers (e.g. Na/H and Na/Ca; 3) neocortical neurons obtained from animals chronically exposed to low O2 postnatally are more vulnerable to acute graded O2/glucose limitation than naive neurons and that this is due to an increase in Na+ influx via up-regulated expression of exchangers and 4) the increased vulnerability in exposed neocortical neurons to O2/glucose deprivation is the result of a faster depletion of high energy metabolites caused by an increased Na+ load. Using techniques and approaches that are operative in our laboratories such as electrophysiologic, molecular biologic techniques and magnetic resonance spectroscopy, we will be able to address all 4 hypotheses. Although we realize that neuronal responsiveness to low O2 is very complex, our long term objectives are to intervene with this system In order to prolong neuronal survival or prevent nerve cell injury. We believe that these current studies are critical steps in the overall understanding of neuronal response and adaptation to short and long term stress.