Human Ghrelin As An Effective Mitigator of Acute Radiation Injury

描述（由申请人提供）：SBIR I期提案旨在证明开发一种新型有效治疗方法的可行性，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件以及恐怖分子辐射照射场景中。急性辐射综合征是在全身或部分身体受到高剂量辐射后发生的。尽管我们对急性放射损伤的病理生理学的理解有了进步，但对急性放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，对于患有急性辐射损伤的患者，存在对有效的新型缓解剂的迫切未满足的医疗需求。胃肠道肽Ghrelin首先被鉴定为生长激素促分泌素受体1a型（即，生长激素释放肽受体）。最初报道Ghrelin通过刺激中枢神经系统中的Ghrelin受体来诱导生长激素释放。大量的证据表明，由中枢和外周生长素释放肽受体介导的生长素释放肽的其他生理特性。虽然人类生长激素释放肽已被证明是有益的，在某些疾病的条件下，它仍然是未知的，这种肽是否可以减轻急性辐射综合征。为了研究这一点，成年雄性大鼠暴露于10-戈伊全身照射（TBI）。我们的初步数据表明，TBI后6小时给予人生长素释放肽（即，早期治疗）降低死亡率。然而，仍然不清楚延迟施用人生长素释放肽（其更临床相关）是否也降低TBI诱导的死亡率。因此，我们假设TBI后延迟给予人生长素释放肽可减轻组织损伤并提高存活率。该SBIR第一阶段项目的主要目标是证明开发和商业化人生长激素释放肽作为有效缓解剂（辐射后24小时或更晚）在降低急性辐射暴露后大规模死亡率方面的可行性。通过评估1）TBI后生长素释放肽组织损伤的剂量-反应效应; 2）人生长素释放肽对TBI诱导的死亡率的剂量-反应效应和时间过程;和3）人生长素释放肽在健康和辐照动物中的药代动力学，确定人生长素释放肽的最佳剂量（延迟治疗）。我们的最终目标（SBIR第二阶段及以后）是获得人类生长激素释放肽的商业利用，作为一种安全有效的缓解急性辐射损伤的人。 公共卫生相关性：在2001年9月11日恐怖主义袭击之后，滥用电离辐射或核装置作为恐怖主义武器被认为是一个重大的公共卫生威胁。尽管我们对急性放射损伤的病理生理学的理解有了进步，但对急性放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资料很少。因此，对于患有急性辐射损伤的人来说，存在对新颖且有效的缓解剂的迫切未满足的医疗需求。

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.