脑卒中诱发内源性红花菜豆酸对神经细胞保护的分子机制研究

This proposal is designed to investigate stroke-induced endogenous Phaseic Acid (PA) and its molecular mechanisms in neuroprotection. PA is a metabolite of a plant stress hormone Abscisic Acid (ABA). Our pilot studies discovered that transient middle cerebral artery occlusion/reperfusion (MCAO) induced the production of a large amount of PA in the brain. Studies using mass spectrometry, biochemistry, electrophysiology and other methods showed that PA was mainly distributed in the interstitial tissue and cerebrospinal fluid of MCAO brain and may function as an endogenous neuroprotective molecule during MCAO recovery. However, the molecular mechanisms and the physiological functions of PA in stroke brain are unclear. We will make use of in vitro cultured primary neurons, brain slices and mouse MCAO animal model to determine whether PA plays a neuroprotective role through uncompetitive inhibition of NMDA receptors, activation of microglia or up-regulation of autophagy processes. These studies will provide evidence to determine whether PA is an endogenous protective molecule in stroke brain. More importantly, this investigation will, in the long-term, shed new light on the molecular mechanism of brain damage occurring in stroke and open new doors for development of novel biomarkers and drugs for stroke therapeutics.

本课题针对脑卒中在大脑内诱导产生的一种脱落酸 - 红花菜豆酸(Phaseic Acid，PA)保护神经细胞的分子机制开展研究。PA是植物应激激素脱落酸(Abscisic Acid, ABA)的代谢产物，其在动物大脑内的生理和病理功能不清楚。本课题组最新研究发现，小鼠中动脉栓塞局灶缺血/再灌注（MCAO）诱发脑室脉络丛产生大量PA。通过质谱、生物化学、电生理等方法分析发现PA可能是大脑内源性的神经保护分子。我们将利用体外培养原代神经细胞、离体脑片、小鼠中动脉栓塞局灶缺血/再灌注动物模型，深入研究PA是否通过调节神经细胞NMDA受体、小胶质细胞激活或者神经细胞自噬等过程对脑卒中引起的神经细胞死亡起到保护作用，为最终确定PA是否为脑卒中诱发的内源性应激保护分子提供理论依据。研究的长期目标是确定PA作为脑卒中新的药物治疗分子靶点。此研究无文献报道，具有较高的前沿性、技术创新性和科学价值。

本课题针对红花菜豆酸(Phaseic Acid，PA)保护神经细胞的分子机制开展研究。本课题组研究发现，小鼠中动脉栓塞局灶缺血/再灌注（MCAO）诱发脑室脉络丛产生大量PA。通过质谱、生物化学、电生理等方法分析发现PA可能是大脑内源性的神经保护分子。利用体外培养原代神经细胞、离体脑片、小鼠中动脉栓塞局灶缺血/再灌注动物模型，证明PA调节神经细胞NMDA受体和小胶质细胞激活过程对脑卒中引起的神经细胞死亡起到保护作用，确定了PA为脑卒中诱发的内源性应激保护分子。本研究的长期目标是确定PA作为脑卒中新的药物治疗分子靶点。研究结果发表在JBC， Neurobiology of Disease等核心期刊， 共5篇; 申请专利2项，获得一项； 培养硕士（谢承滨、毕业）、博士（马佺、在读）、博士后（出站）各一名。