Neuroprotective Effect of Ginkgo Biloba and its Bioactive Components Ischemia

描述(由申请人提供)：我在神经外科，特别是在小动物模型方面的专业知识和技能，加上我对草药和蛋白质组学的知识，对于推动中风和缺血性脑损伤领域的研究至关重要。由于中风是美国第三大常见死因，这一领域的研究非常重要。我为这个临床相关的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，并一直在优化一个永久性的缺血模型。我已经用这两种方法测试了其他标准化的草本植物提取物及其生物活性成分对中风的有益特性。我的长期目标包括研究天然产品，如银杏叶(EGb 761)，以找到预防和治疗中风和脑缺血相关损伤的新机制。在开始我第五年的博士后培训时，我的直接目标是成为一名独立研究人员，从事与缺血相关的神经元损伤的尖端研究。除了我在中风和草药方面的经验外，这项提议还将让我完成行为科学和分子生物学方面的培训，这是实现我独立职业目标所必需的。我将与我的导师多尔博士合作，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，并有经过证明的培训研究员的记录。培训环境还包括约翰·霍普金斯医学院行为神经科学、中风和衰老方面的顶尖研究人员团队。K99/R00奖将让我有时间和必要的支持来实现我的研究目标。本研究的主要目的是通过建立永久性、暂时性和全局性脑缺血模型来研究银杏叶提取物在脑缺血损伤中的神经保护作用及其机制。我们已经积累的证据表明，血红素加氧酶1(HO1)的活性可以减少缺血性脑损伤，我们假设EGB通过诱导HO1来提供神经保护。为了确定HO1在EGB神经保护中的作用，我们将野生型小鼠和HO1靶向缺失(HOT‘“)小鼠置于缺血模型中，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。我们将通过在不同的体外和体内缺血模型中测量脑血流量、海马细胞死亡、HO1的表达和功能结果来解决可能的保护机制。这项研究计划将通过1)确定银杏叶提取物在治疗或预防中风相关损伤方面的疗效，2)确定使用银杏叶提取物的最佳剂量和时间框架，以及3)为临床医生和他们的患者提供有关预防性使用银杏叶提取物的信息，从而具有直接的临床前意义。

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.