Molecular basis of hyperhomocysteinemia induced brain injury in ischemic stroke

高同型半胱氨酸血症是一种常见的代谢性疾病，可导致总的同型半胱氨酸水平显著增加， 血浆同型半胱氨酸尽管FDA强制要求食品中添加叶酸， 尽管高同型半胱氨酸水平，高同型半胱氨酸血症在老年人群中的发病率仍然相当大。这是 这主要是由于随着年龄的增长，营养吸收减少和代谢功能下降。 流行病学研究已经确定，高同型半胱氨酸血症是神经系统疾病的危险因素。 然而，高同型半胱氨酸血症对神经系统疾病预后的直接影响尚不清楚。 我们的研究结果表明，高同型半胱氨酸血症状态下的缺血性损伤导致同时激活 涉及GluN 2A-NMDAR激活的新信号通路， 加重缺血性脑损伤。我们研究的长期目标是开发治疗干预措施， 减少高同型半胱氨酸血症对脑缺血和相关神经退行性变的不利影响 紊乱本特定申请的目的是描述GluN 2A-NMDAR介导的NMDAR是否是一种靶基因。 神经炎症在缺血性脑损伤的恶化中起着核心作用， 高同型半胱氨酸血症中心假设是在高同型半胱氨酸血症条件下， GluN 2A-NMDAR介导的促炎介质MCP-1和PGE 2从神经元的过度释放 导致缺血后小胶质细胞活化和外周免疫细胞浸润的增强。的 提出的研究将使用（1）原代神经元培养物来描绘信号级联，下游的 同型半胱氨酸-GluN 2A-NMDAR刺激，参与增加MCP-1的表达和释放， 来自神经元的PGE 2;（2）高同型半胱氨酸血症大鼠和小鼠，以及一系列条件性基因敲除小鼠 评估GluN 2A-NMDAR在缺血后炎症反应增强中的作用， 高同型半胱氨酸血症动物;和（3）磁共振成像（MRI）和一系列行为测试， 评估缺血后抑制GluN 2A-NMDAR信号通路在减少脑缺血中的长期功效。 高同型半胱氨酸血症动物的脑损伤这项研究具有重要意义，因为它将填补一个 知识差距对于未来设计新的治疗靶点以减轻卒中严重程度至关重要 高同型半胱氨酸血症状态下的结局。

Hyperhomocysteinemia is a common metabolic disorder that causes significant increase in the total level of plasma homocysteine. In spite of the FDA-mandated fortification of food with folic acid, as an attempt to lower homocysteine level, the incidence of hyperhomocysteinemia in the elderly population is still quite large. This is mainly due to lowered nutritional absorption and decreased metabolic function with advanced age. Epidemiological studies have established that hyperhomocysteinemia is a risk factor for neurological diseases. However, the direct impact of hyperhomocysteinemia on the outcome of neurological diseases is still not known. Our findings now show that ischemic insult under hyperhomocysteinemic condition leads to concurrent activation of a novel signaling pathway involving GluN2A-NMDAR activation that in conjunction with the canonical pathway exacerbates ischemic brain injury. The long-term goal of our research is to develop therapeutic interventions for reducing the adverse effect of hyperhomocysteinemia on cerebral ischemia and related neurodegenerative disorders. The objective of this particular application is to delineate whether GluN2A-NMDAR mediated neuroinflammation plays a central role in the exacerbation of ischemic brain damage under hyperhomocysteinemic condition. The central hypothesis is that under hyperhomocysteinemic condition, GluN2A-NMDAR-mediated excessive release of the pro-inflammatory mediators MCP-1 and PGE2 from neurons results in augmentation of post-ischemic microglial activation and peripheral immune cell infiltration. The proposed studies will use (1) primary neuronal cultures to delineate the signaling cascade, downstream of homocysteine-GluN2A-NMDAR stimulation, involved in the increased expression and release of MCP-1 and PGE2 from neurons; (2) hyperhomocysteinemic rat and mice, as well as a series of conditional knockout mice to evaluate the role GluN2A-NMDAR in post-ischemic augmentation of inflammatory response in hyperhomocysteinemic animals; and (3) magnetic resonance imaging (MRI) and a battery of behavioral tests to evaluate the long-term efficacy of post-ischemic inhibition of GluN2A-NMDAR signaling pathway in reducing brain damage in hyperhomocysteinemic animals. The proposed research is significant since it will fill a knowledge gap that is critical for future designing of novel therapeutic targets to mitigate the severity of stroke outcome under hyperhomocysteinemic condition.