Treatment of stroke in young and aged rats using Thymosin beta4

使用胸腺素 beta4 治疗年轻和老年大鼠中风

• 批准号: 8306097
• 负责人: DANIEL C MORRIS
• 金额: $ 27.03万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8306097
• 关键词: Actins; Age; Animals; Applications Grants; Arteries; Blood Clot; Blood coagulation; Brain Part; Cardiac; Cells; Cerebral Ischemia; Cerebrovascular Circulation; Clinical; Cornea; Data; Dermal; Dose; Drug Delivery Systems; Elderly; Epidermal Growth Factor Receptor; Healed; Hour; Human; Ischemic Stroke; Measures; Mediating; Middle Cerebral Artery Occlusion; Modeling; Myocardial Infarction; Nervous System Physiology; Neurologic; Neurological outcome; Oligodendroglia; Outcome; Paralysed; Pharmaceutical Preparations; Proteins; Rattus; Safety; Stem cells; Stroke; Symptoms; Testing; Therapeutic; Thymosin; Time; Treatment Efficacy; aged; angiogenesis; axonal sprouting; central nervous system injury; drug testing; functional improvement; healing; improved; innovation; juvenile animal; migration; mortality; neurogenesis; neurorestoration; novel; phase 1 study; post stroke; pre-clinical; response; subventricular zone; thymosin beta(4); white matter

DESCRIPTION (provided by applicant): This application proposes a novel concept for the treatment of stroke by testing the actin-sequestering protein Thymosin B4 (TB4) in a rat model of embolic stroke. T~4 improves cardiac function after myocardial infarction and promotes dermal and cornea healing. We will use a well-established embolic stroke model to optimize the dose and determine the therapeutic window of administration of TB4 by testing functional neurological outcome in both young and aged rats. Our preliminary data demonstrate that TB4 has the potential for treatment of stroke. Administration of TB4 24 hours after stroke onset improves functional neurological outcome in a rat model of embolic stroke. Our fundamental hypothesis is that treatment with TB4 promotes axonal remodeling by stimulation of oligodendrocyte progenitor cells (OPCs) in the subventricular zone (SVZ) and in the intact white matter in both young and aged rats. Oligodendrocytes (OLs) are highly vulnerable to focal cerebral ischemia and our preliminary data suggest that TB4 increases migration and differentiation of OPCs resulting in improved outcome. [In addition, our preliminary data suggests that the epidermal growth factor receptor (EGF-R) likely mediates the effect of TB4 on OPCs.] The innovation of TB4 in the treatment of stroke is that TB4 acts a neurorestorative agent, Neurorestorative agents are unique in that they act on intact parenchymal cells to stimulate neurogenesis, angiogenesis, axonal sprouting and oligodendrogenesis. Clinically, neurorestorative agents are more practical in that no significant time and therapeutic drug delivery constraints exist and that the drug targets the intact parenchymal cells, with intact cerebral blood flow. TB4 has been tested in both animal and human models with a high safety profile. This application is the first proposal to systematically test TB4 in CNS injury in both young and aged rats. Age is associated with an increased mortality rate and poor neurological outcome compared with young rats after stroke. Moreover, aged animals recover more slowly with reduced functionality when compared to younger animals. Therefore, in order to match the clinical reality of stroke, this application proposes to test TB4 in both young and aged rats. The primary specific aim of this grant application is to determine the therapeutic efficacy of TB4 for treatment of stroke in both young and aged rats. Our specific aims are to: 1) define the optimal dose needed via a dose-response study of TB4 treatment initiated 24 hours after stroke in young and aged rats using neurological outcome as the primary endpoint, 2) determine the therapeutic window of TB4 after stroke in both young and aged rats and [3) to investigate whether epidermal growth factor receptor (EGF-R) mediates TB4 enhanced oligodendrogenesis.] Our results will provide pre-clinical evidence that TB4 is a neurorestorative agent for the treatment of stroke and will provide data for a phase I study in humans.

描述（由申请人提供）：本申请提出了一种新的概念，用于通过在栓塞proct的大鼠模型中测试肌动蛋白序列蛋白胸腺素B4（TB4）来治疗中风的概念。 T〜4改善心肌梗塞后心脏功能，并促进皮肤和角膜愈合。我们将使用良好的栓塞卒中模型来优化剂量并通过测试年轻大鼠和老年大鼠的功能神经系统结局来确定TB4的治疗窗口。我们的初步数据表明，TB4具有中风治疗的潜力。中风发作后24小时的TB4给药可改善栓塞中风大鼠模型的功能神经系统结果。我们的基本假设是，用TB4治疗通过刺激脑室下区（SVZ）的少突胶质细胞祖细胞（OPC）以及在年轻大鼠和老年大鼠的完整白质中促进轴突重塑。少突胶质细胞（OLS）高度容易受到局灶性脑缺血的影响，我们的初步数据表明TB4增加了OPC的迁移和分化，从而改善了预后。 [此外，我们的初步数据表明，表皮生长因子受体（EGF-R）可能介导了TB4对OPC的影响。寡导体发生。在临床上，神经4to剂更实用，因为没有大量的时间和治疗性药物递送约束，并且该药物靶向完整的脑血液流动，靶向完整的实质细胞。 TB4已在具有高安全性的动物和人类模型中进行了测试。该应用是在年轻大鼠和年龄大鼠中系统地测试CNS损伤中TB4的第一个建议。与中风后的年轻大鼠相比，年龄与死亡率升高和神经系统结局差有关。此外，与年轻动物相比，衰老的动物的功能降低恢复得更慢。因此，为了匹配中风的临床现实，该应用建议在年轻大鼠和老年大鼠中测试TB4。该赠款应用的主要目的是确定TB4在年轻大鼠和老年大鼠中治疗中风的治疗功效。我们的具体目的是：1）通过使用神经系统结果作为主要终点，通过对年轻大鼠和年龄大鼠的中风后24小时开始对TB4治疗的剂量反应研究来定义最佳剂量，2）确定在年轻大鼠和衰老大鼠和[3）中的TB4的治疗窗口，以调查ESPERMERMAL和[3）是否增强了ESPERMERMAL GRANTIES CONTERTER FINTER FIRSER（EGERMERMAL）（EGERMERMAL）（EGFR）（EGF-R）我们的结果将提供临床前的证据，表明TB4是中风治疗的神经训练剂，并将为人类I期研究提供数据。