Human Ghrelin As An Effective Mitigator of Acute Radiation Injury

描述(由申请人提供)：这份SBIR第一阶段提案旨在证明开发一种新的、有效的治疗方法的可行性，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件以及恐怖分子辐射暴露的情况下。急性辐射综合征是在全身或局部接受高剂量辐射后出现的。尽管我们对急性辐射损伤的病理生理学的理解有所进展，但对急性辐射综合征的治疗主要是支持性的。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释剂，这种需求尚未得到满足。Ghrelin是一种胃肠道多肽，最初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最初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。大量证据表明，Ghrelin的其他生理特性是由中枢和外周Ghrelin受体介导的。尽管人类Ghrelin已被证明在某些疾病条件下是有益的，但这种多肽是否可以缓解急性辐射综合征仍不清楚。为了研究这一点，成年雄性大鼠接受了10Gy全身照射(TBI)。我们的初步数据显示，在脑损伤后6小时(即非常早期的治疗)给予人Ghrelin可降低死亡率。然而，目前尚不清楚延迟给药人生长激素(临床意义更大)是否也能降低脑损伤引起的死亡率。因此，我们假设在脑外伤后延迟给予人生长激素可以减轻组织损伤并提高存活率。这个SBIR第一阶段项目的主要目标是证明人类Ghrelin作为一种有效的缓释剂(辐射后24小时或更晚)在减少急性辐射暴露后的大量死亡方面的可行性。人Ghrelin(延迟治疗)的最佳剂量(S)将通过以下评估来确定：1)脑创伤后Ghrelin组织损伤的剂量-反应效应；2)人Ghrelin对脑创伤后死亡率的剂量-反应效应和时程；3)人Ghrelin在健康和受辐射动物体内的药代动力学。我们的最终目标(SBIR第二阶段及以后)是使人类Ghrelin作为急性辐射损伤患者的安全有效的缓释剂获得商业应用。 与公共卫生有关：2001年9月11日恐怖袭击发生后，误用电离辐射或核装置作为恐怖主义武器已被认为是对公共卫生的重大威胁。尽管我们对急性辐射损伤的病理生理学的理解有所进展，但对急性辐射综合征的治疗主要是支持性的。关于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，迫切需要一种新颖有效的缓释剂，这种需求尚未得到满足。

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.