Preclinical Testing of Human Ghrelin for the Treatment of Stroke

描述(由申请人提供)：该计划的最终目标是开发一种新的治疗方法，以挽救中风患者的生命。急性中风是美国第三大死亡原因，也是导致成人后天残疾的主要医学原因。每年，约有795,000名美国人经历新发或复发的中风。在美国，每18例死亡中就有1例死于此病。随着人口老龄化，中风护理费用预计将大幅增加。中风护理的直接医疗费用估计将从2010年的283亿美元增加到2030年的956亿美元。尽管中风很普遍，但目前的治疗选择非常有限，中风幸存者仍然面临严重的发病率问题。开发安全有效的治疗中风患者的疗法仍然是制药业面临的主要挑战。人Ghrelin是一种新的胃肠激素，首次被鉴定为生长激素促分泌素受体1a型(即Ghrelin受体)的内源性配体。Ghrelin可以自由地穿过血脑屏障，并被报道通过刺激中枢神经系统中的Ghrelin受体来诱导生长激素释放。然而，充分的证据表明，Ghrelin除了在生长激素释放中发挥作用外，还具有其他生理功能。使用永久性大脑中动脉闭塞(即缺血性中风)的动物模型，我们的初步研究表明，人类Ghrelin治疗改善了神经功能，缩小了梗死面积，并提高了存活率。该项目的主要目标是证明人类Ghrelin作为中风患者新型治疗剂的进一步开发和商业化的可行性。将使用有或没有再灌注的缺血性中风的动物模型。最佳剂量(S)和治疗窗口将通过评估人Ghrelin对脑损伤的剂量依赖效应和人类Ghrelin对中风后有益作用的时程来确定。此外，我们将研究人类Ghrelin对有或无再灌流的缺血性卒中后运动功能损害的长期影响。我们未来的目标(SBIR第二阶段及以后)是将人类Ghrelin作为一种安全有效的中风患者治疗方法进行商业化使用。

DESCRIPTION (provided by applicant): The ultimate objective of this program is to develop a novel therapeutic approach that will save lives of patients with stroke. Acute stroke is the third leading cause of death in the United States and the primary medical cause of acquired adult disability. Each year, ~795,000 Americans experience new or recurrent stroke. It accounts for 1 out of every 18 deaths in the United States. As the population ages, stroke care costs are expected to increase substantially. The direct medical costs for stroke care are estimated to increase from $28.3 billion in 2010 to $95.6 billion in 2030. Despite its prevalence, current treatment options are very limited and stroke survivors still encounter serious morbidity issues. The development of safe and effective therapeutics to treat stroke patients remains a major challenge to the pharmaceutical industry. Human ghrelin, a novel gastrointestinal hormone, was first identified as the endogenous ligand for the growth hormone secretagogue receptor type 1a (i.e., ghrelin receptor). Ghrelin freely crosses the blood brain barrier (BBB) and has been reported to induce growth hormone release through stimulation of ghrelin receptor in the central nervous system. However, sufficient evidence has pointed out other physiological functions of ghrelin in addition to its role in growth hormone release. Using an animal model of permanent middle cerebral artery occlusion (i.e., ischemic stroke), our preliminary studies have shown that human ghrelin treatment improved neurological function, reduced infarct size, and increased survival. The primary objective of this project is targeted towards demonstrating the feasibility o the further development and commercialization of human ghrelin as a novel therapeutic agent for stroke patients. Animal models of ischemic stroke with or without reperfusion will be used. The optimal dosage(s) and therapeutic window will be determined by assessing the dose-dependent effect of human ghrelin on brain injury and the time-course of human ghrelin's beneficial effects after stroke. Furthermore, we will investigate the long-term effect of human ghrelin on motor function impairment after ischemic stroke with or without reperfusion. Our future goal (SBIR Phase II and beyond) is to obtain commercial utilization of human ghrelin as a safe and effective therapy for patients suffering from stroke.