Human Ghrelin as an Effective Mitigator of Acute Radiation Injury

 描述(由申请人提供)：这项SBIR第二阶段提案旨在进一步开发人类Ghrelin作为放射医学对策(MCM)，并在未来得到FDA的批准。核恐怖主义和核电站泄漏的风险仍然很高，两者都可能造成大规模的急性辐射伤害。目前，可用于治疗急性辐射综合征(ARS)的药物有限。人Ghrelin是一种由28个氨基酸组成的多肽激素，对包括内分泌、胃肠(GI)、心血管和免疫系统在内的各种身体系统都有广泛的影响。在我们完成的SBIR第一阶段项目中，我们将大鼠和小鼠暴露在全身照射(TBI)中，并证明了从TBI后24小时开始，皮下注射人Ghrelin 6天，显著提高了它们的存活率，并减少了它们的体重减轻。我们进一步证明，在大鼠身上，人Ghrelin治疗改善了肠道完整性，减少了肠道细胞凋亡和通透性。人类胃促生长素可以大量合成，以满足大规模应急需要。此外，人类Ghrelin已经在几个临床试验中进行了其他疾病适应症的测试，具有极好的安全性。基于我们积极的I期研究结果，我们假设人类Ghrelin可以被开发为一种有效的暴露后缓解急性辐射损伤的药物。在本方案中，我们将使用小鼠辐射损伤模型来确定人Ghrelin治疗GI-ARS和造血性ARS(H-ARS)的剂量修正因子(DMF)。我们还将检查人类Ghrelin在减轻造血和胃肠道损伤方面的作用。此外，我们将在非人类灵长类动物(NHP)中进行一项探索性研究，以评估人类Ghrelin治疗对胃肠道指数和血液学辐射反应的影响。这些拟议的研究将为人类Ghrelin作为一种主要针对GI-ARS的新型放射MCM的疗效提供关键信息。我们的最终目标是获得FDA的批准，使用人类Ghrelin作为一种安全有效的治疗辐射紧急情况下急性辐射损伤的方法。

 DESCRIPTION (provided by applicant): This SBIR Phase II proposal is intended to further develop human ghrelin as a radiation medical countermeasure (MCM) to be approved by the FDA in the future. The risks of nuclear terrorism and nuclear power plant leaks still remain high, both of which can cause acute radiation injury on a large scale. Currently, there are limited drugs available to treat acute radiation syndrome (ARS). Human ghrelin is a 28-amino acid peptide hormone with broad effects on various body systems, including the endocrine, gastrointestinal (GI), cardiovascular, and immune systems. In our completed SBIR Phase I project, we have exposed rats and mice to total body irradiation (TBI) and demonstrated that subcutaneous administration of human ghrelin for 6 days, starting at 24 h post-TBI, significantly increased their survival rates and reduced their body weight loss. We further demonstrated, in the rat, that treatment with human ghrelin improved intestinal integrity and reduced gut apoptosis and permeability. Human ghrelin can be synthesized in large quantity for mass emergency needs. Moreover, human ghrelin has been tested in several clinical trials for other disease indications with an excellent safety profile. Based on our positive Phase I results, we hypothesize that human ghrelin can be developed as an effective post-exposure mitigator for acute radiation injury. In this proposal, we will use the mouse model of radiation injury to identiy the dose modification factor (DMF) of human ghrelin to treat GI-ARS and hematopoietic ARS (H- ARS). We will also examine human ghrelin's effect to attenuate hematopoietic and GI damages. In addition, we will conduct an exploratory study in non-human primates (NHP) to evaluate the effect of human ghrelin treatment on the GI and hematology response to radiation exposure. These proposed studies should provide crucial information on the efficacy of human ghrelin as a novel radiation MCM primarily targeting GI-ARS. Our ultimate goal is to obtain the FDA approval to use human ghrelin as a safe and effective treatment for people with acute radiation injury after a radiation emergency.