Preclinical Testing of Human Ghrelin for the Treatment of Stroke

描述（由申请人提供）：本项目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，也是成人获得性残疾的主要医学原因。每年约有79.5万美国人经历新的或复发性中风。在美国，每18名死者中就有1人死于糖尿病。随着人口老龄化，中风治疗费用预计将大幅增加。据估计，中风治疗的直接医疗费用将从2010年的283亿美元增加到2030年的956亿美元。尽管其流行，目前的治疗选择非常有限，中风幸存者仍然遇到严重的发病率问题。开发安全有效的治疗中风患者的药物仍然是制药业面临的主要挑战。人胃饥饿素（ghrelin）是一种新型胃肠道激素，最早被发现是生长激素促分泌素受体1a型（即胃饥饿素受体）的内源性配体。胃饥饿素可以自由穿过血脑屏障（BBB），据报道通过刺激中枢神经系统的胃饥饿素受体诱导生长激素释放。然而，已有足够的证据指出，除了ghrelin在生长激素释放中的作用外，它还有其他的生理功能。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，人类胃饥饿素治疗改善了神经功能，减少了梗死面积，提高了生存率。该项目的主要目标是证明人类胃饥饿素作为中风患者的新型治疗药物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脑卒中动物模型。最佳剂量和治疗窗口期将通过评估人胃饥饿素对脑损伤的剂量依赖效应和脑卒中后人胃饥饿素有益作用的时间过程来确定。此外，我们将研究人胃饥饿素对缺血性卒中伴或不伴再灌注后运动功能损伤的长期影响。我们未来的目标（SBIR II期及以后）是获得人类胃饥饿素的商业利用，作为卒中患者安全有效的治疗方法。

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.