权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Neurorecovery Effect of Novel Modified Erythropoietin on Ischemic Brain Injury

新型改良促红细胞生成素对缺血性脑损伤的神经恢复作用

基本信息

批准号：
8837617
负责人：
GUODONG CAO
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8837617
关键词：
Acute Adult Adverse effects Alteplase Amino Acids Attenuated Binding Blood Blood Platelets Cause of Death Cell Culture Techniques Cell Death Cerebral Ischemia Clinic Clinical Trials Coagulation Process Data Dose Erythrocytes Erythropoietin Generations Hematocrit procedure Hormones Hour In Vitro Infarction Injection of therapeutic agent Injury Ischemia Ischemic Brain Injury Ischemic Stroke Kidney MAP Kinase Gene MAPK3 gene Mediating Middle Cerebral Artery Occlusion Modeling Mus Mutation Neurologic Neurological outcome Neurons Pathway interactions Patients Pharmaceutical Preparations Production Reagent Recovery of Function Regimen Research Risk Factors Signal Pathway Stroke Testing Therapeutic abstracting acute stroke angiogenesis brain repair brain tissue clinical application clinically relevant disability high risk improved in vitro Model in vivo in vivo Model mutant neurogenesis neurological recovery neuroprotection novel patient population post stroke white matter injury

项目摘要

Abstract Stroke is the nation's third leading cause of death and the most common cause of permanent disability in adults. Thus far, the only drug that has been used successfully to treat acute stroke in the clinic is the clot- dissolving drug tissue plasminogen activator (tPA). However, tPA must be administered within 3 hours of the onset of an ischemic stroke, making it a viable treatment for less than 6% of patients. Thus, strategies providing for a wider inclusion of patient populations are needed for the treatment of stroke. Erythropoietin (EPO) has recently emerged as a promising candidate both for neuroprotection and neurorecovery in ischemic stroke. EPO has robust neuroprotective effects in both in vitro and in vivo models of ischemic injury. A recent clinical trial demonstrated the beneficial effects of administering EPO in patients with acute ischemic stroke. Thus, a neuroprotective approach using EPO in stroke, especially in treatment of patients who are not suitable for tPA treatment, represents a potentially exciting clinical application. Excitingly, our recent study indicated that EPO administration initiated at 48 hours after ischemia did not reduce brain tissue loss, but stimulated neurogenesis and oligodendrogenesis, attenuated white matter injury, and significantly improved neurological recovery after ischemia, suggesting that EPO is a promising therapeutic reagent for the neurological functional recovery of poststroke patients. However, large doses and multiple administration of EPO are required for the treatment of stroke, especially for the delayed treatment. Such a regimen of EPO administration may potentially result in multiple high risk factors for stroke patients, such as increases in hematocrit and quantity of platelets, increasing the likelihood of secondary-infarction. Accordingly, alternate strategies to reduce erythropoietic activity and other potential side effects of EPO will greatly improve its clinical applications for the treatment of stroke patients. We have successfully generated a novel mutant EPO (MEPO) containing a single amino acid mutation which completely lacks erythropoietic activity. Importantly, MEPO has neuroprotective effects and retains the ability to stimulate the neurogenesis with similar efficacies as wild-type EPO. Therefore, the objective of this proposal is to test the neurorecovery effect of MEPO lacking erythropoietic activity after a delayed administration of MEPO in the clinically relevant middle cerebral artery occlusion (MCAO) model. The following specific aims are proposed: Aim 1: To test the hypothesis that delayed administration of MEPO lacking erythropoietic activity improves neurological outcomes after ischemic injury. Focal cerebral ischemia will be induced by MCAO for 60 min. EPO and MEPO will be injected intraperitoneally into mice in a delayed manner. These studies will determine: 1) whether delayed injection of MEPO results in improved neurological outcomes after ischemia, and 2) whether delayed injection of MEPO reduces brain tissue loss. Aim 2: To test the hypothesis that MEPO mediates the neurorecovery effect via enhancing neurovescular remodeling and attenuating white matter injury. We will test: 1) whether delayed injection of MEPO enhances angiogenesis and neurogenesis; 2) whether delayed injection of MEPO attenuates white matter injury and 3) whether delayed administration of MEPO inhibits cell death after ischemia. Aim 3: To test the hypothesis that neurogenesis/oligodendrogenesis effects of MEPO is mediated by EPO/¿CR heterocomplex via PI3K/Akt and MAPK/Erk1/2 signaling pathways. We will test whether MEPO mediates neurogenesis/oligodendrogenesis via binding to EPO/¿CR heterocomplex and activating PI3K/Akt and MAPK/Erk1/2 pathways in an in vitro model of neurogenesis in neurosphere cultures as well as in the murine MCAO model.

摘要中风是美国第三大死亡原因，也是导致永久残疾的最常见原因。成年人了到目前为止，临床上唯一成功用于治疗急性中风的药物是血栓- 溶解药物组织纤溶酶原激活剂（tPA）。但是，tPA必须在注射后3小时内给药。缺血性中风的发作，使其成为不到6%的患者的可行治疗方法。因此，战略需要提供更广泛的患者群体以用于中风的治疗。促红细胞生成素（EPO）最近已成为神经保护和神经保护的有希望的候选物。缺血性卒中的神经恢复EPO在体外和体内模型中都具有强大的神经保护作用缺血性损伤最近的一项临床试验表明，急性缺血性中风因此，在中风中使用EPO的神经保护方法，特别是在治疗中，不适合tPA治疗的患者中，代表了潜在的令人兴奋的临床应用。令人兴奋的是，我们最近的研究表明，缺血后48小时开始的EPO给药，减少脑组织损失，但刺激神经发生和少突神经发生，减少白色物质损伤，并显着改善缺血后的神经恢复，这表明EPO是一种有前途的一种脑卒中患者神经功能恢复的治疗剂。然而，大剂量 EPO的多次给药是治疗中风所必需的，尤其是对于迟发性治疗这种EPO给药方案可能潜在地导致多种高风险因素，中风患者，如红细胞压积和血小板数量增加，继发性梗死因此，降低红细胞生成活性和其他潜在的 EPO的副作用将大大提高其治疗中风患者的临床应用。我们有成功地产生了含有单个氨基酸突变的新突变EPO（MEPO），完全缺乏红细胞生成活性。重要的是，MEPO具有神经保护作用，并保留了具有与野生型EPO类似的功效的刺激神经发生的能力。因此，该建议是为了测试MEPO缺乏红细胞生成活性的神经恢复效果，在临床相关的大脑中动脉闭塞（MCAO）模型中给予MEPO。的建议的具体目标如下：目的1：验证延迟给予MEPO缺乏红细胞生成活性的假设改善缺血性损伤后的神经功能结局。局灶性脑缺血将由将EPO和MEPO以延迟的方式腹膜内注射到小鼠中。这些研究将确定：1）延迟注射MEPO是否会改善神经系统结局缺血后，和2）延迟注射MEPO是否减少脑组织损失。目的2：验证MEPO通过增强脑缺血再灌注损伤后的神经功能恢复而介导脑缺血再灌注损伤后神经功能恢复的假说。神经血管重塑和减轻白色物质损伤。我们将测试：1）是否延迟注射MEPO促进血管生成和神经发生; 2）延迟注射MEPO是否减轻白色物质损伤和3）延迟给予MEPO是否抑制细胞死亡，缺血目的3：验证MEPO介导的神经发生/少突胶质细胞发生作用的假说 EPO/CR异源复合物通过PI 3 K/Akt和MAPK/Erk 1/2信号通路介导。我们将测试 MEPO通过与EPO/CR异源复合物结合并激活 PI 3 K/Akt和MAPK/Erk 1/2通路在神经球培养物神经发生体外模型中的作用如在鼠MCAO模型中。