Human Ghrelin As An Effective Mitigator of Acute Radiation Injury

描述（由申请人提供）：该SBIR I期提案旨在证明开发一种新颖有效的治疗方法的可行性，该方法可以挽救辐射损伤患者的生命。急性辐射损伤可能发生在各种事故中，也可能发生在恐怖辐射暴露情景中。急性辐射综合征是在全身或局部受到高剂量辐射后发生的。尽管我们对急性辐射损伤的病理生理学的理解有所进展，但急性辐射综合征的管理主要是支持性的。关于急性辐射损伤的具体治疗方法的信息很少。因此，对于急性辐射损伤患者来说，迫切需要一种有效的新型缓解剂。胃饥饿素（Ghrelin）是一种胃肠道肽，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。Ghrelin最初被报道通过刺激中枢神经系统的Ghrelin受体来诱导生长激素的释放。大量证据表明，胃饥饿素的其他生理特性是由中枢和外周胃饥饿素受体介导的。虽然人类胃饥饿素已被证明对某些疾病有益，但这种肽是否能减轻急性辐射综合征仍不清楚。为了研究这一点，将成年雄性大鼠暴露于10 gy全身照射（TBI）。我们的初步数据显示，在脑外伤后6小时（即非常早期治疗）使用人类胃饥饿素可降低死亡率。然而，目前尚不清楚是否延迟给药人类胃饥饿素（这与临床更相关）也能降低脑外伤引起的死亡率。因此，我们假设脑外伤后延迟给药人类胃饥饿素可以减轻组织损伤并提高生存率。该SBIR一期项目的主要目标是证明人类饥饿素作为一种有效的缓解剂（辐射后24小时或更晚）在减少急性辐射暴露情景后大量死亡率方面的开发和商业化可行性。人类胃饥饿素（延迟治疗）的最佳剂量将通过评估1)脑外伤后胃饥饿素组织损伤的剂量-反应效应来确定；2)人胃饥饿素对脑外伤致死的量效效应和时间过程；3)人胃饥饿素在健康和辐照动物体内的药代动力学。我们的最终目标（SBIR II期及以后）是获得人类胃饥饿素的商业利用，作为急性辐射损伤患者安全有效的缓解剂。

DESCRIPTION (provided by applicant): This SBIR Phase I proposal is intended to demonstrate the feasibility of developing a novel and effective therapeutic approach that can save lives of people with radiation injury. Acute radiation injury may occur in various incidents as well as the terrorist radiation exposure scenario. Acute radiation syndrome develops after whole-body or a partial-body irradiation with a high dose of radiation. Despite advances in our understanding of the pathophysiology of acute radiation injury, the management of acute radiation syndrome is mainly supportive. Very little information is available on the specific treatment approaches to acute radiation injury. As such, there is an urgent unmet medical need for an effective novel mitigator for patients with acute radiation injury. Ghrelin, a gastrointestinal peptide, was first identified as an endogenous ligand for the growth hormone secretagogue receptor type 1a (i.e., ghrelin receptor). Ghrelin was originally reported to induce growth hormone release through stimulation of ghrelin receptors in the central nervous system. A large body of evidence has indicated other physiological properties of ghrelin mediated by the central and peripheral ghrelin receptors. Although human ghrelin has been shown to be beneficial in certain disease conditions, it remains unknown whether this peptide can mitigate acute radiation syndrome. To study this, adult male rats were exposed to 10-Gy total body irradiation (TBI). Our preliminary data have shown that administration of human ghrelin 6 h after TBI (i.e., very early treatment) reduced mortality. However, it remains unknown whether delayed administration of human ghrelin (which is more clinically relevant) reduces TBI-induced mortality as well. We, therefore, hypothesize that delayed administration of human ghrelin after TBI attenuates tissue injury and improves survival. The primary objective of this SBIR Phase I project is targeted towards demonstrating the feasibility of the development and commercialization of human ghrelin as an effective mitigator (24 h post-radiation or later) in reducing the massive mortality after acute radiation exposure scenario. The optimal dosage(s) of human ghrelin (delayed treatment) will be determined by assessing 1) the dose-response effect of ghrelin tissue injury after TBI; 2) the dose-response effect and time-course of human ghrelin on TBI-induced mortality; and 3) the pharmacokinetics of human ghrelin in healthy and irradiated animals. Our ultimate goal (SBIR Phase II and beyond) is to obtain commercial utilization of human ghrelin as a safe and effective mitigator for people with acute radiation injury. PUBLIC HEALTH RELEVANCE: In the wake of the September 11, 2001 terrorist attacks, the misuse of ionizing radiation or nuclear devices as weapons of terrorism has been recognized as a major public health threat. Despite advances in our understanding of the pathophysiology of acute radiation injury, the management of acute radiation syndrome is mainly supportive. Very little information is available on the specific therapeutic approaches to radiation injury. Thus, there is an urgent unmet medical need for a novel and effective mitigator for people with acute radiation injury.