Molecular basis of hyperhomocysteinemia induced brain injury in ischemic stroke

描述(申请人提供)：高同型半胱氨酸血症是一种常见的代谢紊乱，导致血浆总同型半胱氨酸水平显著增加。尽管FDA规定在食品中添加叶酸，试图降低同型半胱氨酸水平，但高同型半胱氨酸血症在老年人群中的发生率仍然相当高。这主要是由于随着年龄的增长，营养吸收和代谢功能降低所致。新的证据表明，高同型半胱氨酸血症的易感性可能与阿尔茨海默病、帕金森病或急性缺血性中风患者神经元损伤的加重和加速以及随后的脑损伤有关。然而，易患高同型半胱氨酸血症的个体的神经学损害的病理意义或分子基础尚不清楚。我们的发现现在表明，在高同型半胱氨酸血症动物中，轻微的缺血性侮辱会加剧脑损伤。研究结果还表明，同型半胱氨酸依赖的神经毒性涉及一种新的信号通路，该通路是通过刺激NR2A-NMDA受体介导的。我们研究的长期目标是开发治疗干预措施，以减少高同型半胱氨酸血症对脑缺血和相关神经退行性疾病的不利影响。这一特殊应用的目的是研究同型半胱氨酸诱导的神经元损伤的分子基础，并评估高同型半胱氨酸血症动物的缺血性脑损伤和神经功能障碍的长期进展。中心假设是，同型半胱氨酸-NR2A-NMDA受体信号触发了有害的信号级联反应，与缺血诱导的通路协同作用，加剧了脑损伤。拟议的研究将使用(1)原代神经元培养来描述同型半胱氨酸依赖的NR2A-NMDA受体刺激后激活的有害信号级联；以及(2)磁共振成像(MRI)和一系列行为测试，以纵向评估高同型半胱氨酸血症动物的缺血性脑损伤和神经结局。这项研究将进一步评估在高同型半胱氨酸血症的情况下，干扰NR2A-NMDA受体依赖的信号传递是否可以将与中风相关的脑损伤降至最低。这项拟议的研究意义重大，因为它将为高同型半胱氨酸血症在缺血性脑损伤进展中的作用提供第一个直接证据。了解同型半胱氨酸诱导神经元损伤的潜在机制(S)将有助于开发潜在的靶点，以减轻高同型半胱氨酸血症在脑缺血和其他年龄相关性神经退行性疾病中的不利影响。

DESCRIPTION (provided by applicant): Hyperhomocysteinemia is a common metabolic disorder that causes a 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 levels, 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. Emerging evidence suggest that pre-disposition to hyperhomocysteinemic conditions may be associated with aggravation and acceleration of neuronal injury and subsequent brain damage in individuals suffering from Alzheimer's and Parkinson's diseases or acute ischemic stroke. However the pathological implications or the molecular basis of neurological insult in individuals predisposed to hyperhomocysteinemia is yet unknown. Our findings now show that a mild ischemic insult in hyperhomocysteinemic animals exacerbates brain injury. The findings also show that homocysteine-dependent neurotoxicity involves a novel-signaling pathway that is mediated through NR2A- NMDA receptor stimulation. 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 objectives of this particular application are to examine the molecular basis of homocysteine induced neuronal injury and evaluate the long-term progression of ischemic brain damage and neurological deficits in hyperhomocysteinemic animals. The central hypothesis is that homocysteine-NR2A-NMDA receptor signaling triggers a deleterious signaling cascade that acts in concert with ischemia-induced pathways to exacerbate brain injury. The proposed studies will use (1) primary neuronal cultures to delineate the deleterious signaling cascades that are activated following homocysteine-dependent NR2A-NMDA receptor stimulation; and (2) Magnetic resonance imaging (MRI) and a battery of behavioral tests for longitudinal evaluation of ischemic brain injury and neurological outcome in hyperhomocysteinemic animals. The study will further evaluate whether disruption of NR2A-NMDA receptor dependent signaling could minimize brain damage associated with stroke under hyperhomocysteinemic conditions. The proposed research is significant since it will provide the first direct evidence for the role of hyperhomocysteinemia in the progression of ischemic brain injury. Understanding the underlying mechanism(s) of homocysteine induced neuronal injury will facilitate the development of potential targets to attenuate the detrimental effects of hyperhomocysteinemia in cerebral ischemia and other age-related neurodegenerative disorders.