Neuroprotective Effect of Ginkgo Biloba and its Bioactive Components Ischemia

描述（由申请人提供）：我在神经外科方面的专业知识和技能，特别是在小动物模型方面，以及我在草药和蛋白质组学方面的知识，对于中风和缺血性脑损伤领域的研究进展至关重要。由于中风是美国第三大常见死因，因此该领域的研究非常重要。我对这个临床相关问题做出了许多贡献。例如，我最近发表了一种在小鼠中产生短暂性中风的优化方法，并且还一直在优化永久性缺血模型。我使用这两种方法来测试其他标准化的草药植物提取物及其生物活性成分对抗中风的有益特性。我的长期目标包括研究银杏叶 (EGb 761) 等天然产品，以找到预防和治疗中风和缺血相关脑损伤的新机制。在开始第五年的博士后培训时，我的近期目标是成为缺血相关神经元损伤前沿研究的独立研究员。除了我在中风和草药方面的经验之外，这个建议将使我能够完成行为科学和分子生物学方面的培训，这是实现我的独立职业目标所必需的。我将与我的导师 Dore 博士一起工作，他在与中风和其他神经退行性疾病相关的神经元功能障碍方面拥有丰富的专业知识，并且拥有良好的培训研究员记录。培训环境还包括约翰霍普金斯大学医学院行为神经科学、中风和衰老领域的顶尖研究人员团队。 K99/R00 奖项将为我提供实现研究目标所需的时间和支持。该项目的主要目标是通过使用永久性、短暂性和全局缺血模型来确定 EGb 在缺血性脑损伤中的神经保护作用和作用机制。我们已经积累了证据表明血红素加氧酶 1 (HO1) 活性可减少缺血性脑损伤，并且我们假设 EGb 通过诱导 HO1 提供神经保护。为了确定 HO1 在 EGb 神经保护中的作用，我们将对野生型小鼠和 HO1 靶向缺失小鼠 (HOT'") 进行缺血模型，并比较 EGb 治疗前后对损伤大小的影响。我们还将优化治疗剂量和窗口。我们将通过测量各种体外和体内缺血模型中的脑血流、海马细胞死亡、HO1 表达和功能结果来探讨可能的保护机制。该研究计划将具有直接的临床前研究通过 1) 确定 EGb 在治疗或预防中风相关损伤中的功效，2) 确定 EGb 使用的最佳剂量和时间范围，以及 3) 为临床医生及其患者提供有关预防性使用银杏提取物 EGb 的信息。

DESCRIPTION (provided by applicant): My expertise and skill in neurosurgery, particularly in small animal models, together with my knowledge of herbal drugs and proteomics are essential to the advancement of research in the field of stroke and ischemic brain damage. Because stroke is the third most common cause of death in the US, research in this field is of great importance. I have made a number of contributions to this clinically relevant problem. For example, I have recently published an optimized method for producing transient stroke in mice, and have been optimizing a permanent model of ischemia also. I have used both of these methods to test the beneficial properties of other well standardized herbal plant extracts and their bioactive components against stroke. My long term goals involve researching natural products, such as Ginkgo biloba (EGb 761), to find novel mechanisms for preventing and treating stroke and ischemia-related brain injury. While starting my fifth year of postdoctoral training, my immediate goal is to become an independent researcher in the cutting-edge research of neuronal damage associated with ischemia. In addition to my experience in stroke and herbal medicine, this proposal will allow me to complete my training in behavioral science and molecular biology which is necessary to reach my independent career goals. I will work with my mentor, Dr. Dore, who has extensive expertise in neuronal dysfunction associated with stroke and other neurodegenerative diseases and has a proven record of training fellows. The training environment also involves a team of top researchers in behavioral neuroscience, stroke, and aging at the Johns Hopkins School of Medicine. The K99/R00 award will allow me the time and support necessary to work toward my research goals. The main goal of the proposed project is to determine the neuroprotective effect and mechanism of actions of EGb in ischemic brain injury by using permanent, transient, and global models of ischemia. We have accumulated evidence that heme oxygenase 1 (HO1) activity reduces ischemic brain injury, and we hypothesize that EGb provides neuroprotection by inducing HO1. To determine the role of HO1 in EGb neuroprotection, we will subject wildtype mice and mice with targeted deletion of HO1 (HOT'") to models of ischemia and compare the effect of EGb pre- and post-treatment on injury size. We will also optimize the therapeutic dose and window. We will address possible mechanisms of protection by measuring cerebral blood flow, hippocampal cell death, HO1 expression, and functional outcomes in various in vitro and in vivo ischemia models. This research proposal will have direct pre-clinical relevance by 1) determining the efficacy of EGb in treating or preventing stroke-related injury, 2) determining the optimal dose and time frame for EGb use, and 3) providing information for clinicians and their patients regarding the prophylactic use of Ginkgo extract, EGb.