Human Ghrelin as an Effective Mitigator of Acute Radiation Injury

人类生长素释放肽作为急性辐射损伤的有效缓解剂

• 批准号: 9141294
• 负责人: Weng-Lang Yang
• 金额: $ 98.25万
• 依托单位: THERASOURCE, LLC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-20 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9141294
• 关键词: Accidents; Acute; Amino Acids; Animals; Apoptosis; Attenuated; Autopsy; Bacterial Translocation; Baltimore; Biological Assay; Blood; Body Weight Changes; Body Weight decreased; Bone Marrow; C57BL/6 Mouse; Cardiovascular system; Cessation of life; Citrulline; Clinical Trials; Colony-forming units; Complete Blood Count; Detection; Diarrhea; Disasters; Disease; Dose; Drug Kinetics; Eating; Emergency Situation; Endocrine; FDA approved; Fever; Funding; Future; Goals; Hematology; Hematopoietic; Human; Immune system; Inflammatory; Injury; Intestines; Lethal Dose 50; Macaca mulatta; Maryland; Measurement; Medical; Mesentery; Modeling; Modification; Monitor; Morphology; Mus; Neutropenia; Nuclear; Nuclear Power Plants; Permeability; Pharmaceutical Preparations; Phase; Plasma; Radiation; Radiation Dose-Response Relationship; Radiation Injuries; Radiation Toxicity; Radioactive; Rattus; Risk; Safety; Saline; Serum; Small Business Innovation Research Grant; Survival Rate; Terrorism; Testing; Therapeutic; Time; Universities; War; Whole-Body Irradiation; base; body system; cytokine; effective therapy; gastrointestinal; gastrointestinal system; ghrelin; granulocyte; improved; irradiation; lymph nodes; macrophage; mouse model; nonhuman primate; novel; peptide hormone; phase 1 study; programs; public health relevance; radiation response; subcutaneous; treatment duration

 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.

 描述（由申请人提供）：该 SBIR II 期提案旨在进一步开发人类生长素释放肽，作为未来 FDA 批准的辐射医学对策（MCM）。核恐怖主义和核电站泄漏风险依然较高，可造成大面积急性辐射损伤。目前，可用于治疗急性放射综合征（ARS）的药物有限。人生长素释放肽是一种由 28 个氨基酸组成的肽激素，对多种身体系统具有广泛影响，包括内分泌、胃肠 (GI)、心血管和免疫系统。在我们已完成的 SBIR 第一阶段项目中，我们将大鼠和小鼠暴露于全身照射 (TBI)，并证明从 TBI 后 24 小时开始皮下注射人生长素释放肽 6 天，显着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，在大鼠中，用人生长素释放肽治疗可以改善肠道完整性并减少肠道细胞凋亡和通透性。人类生长素释放肽可以大量合成以满足大规模紧急需求。此外，人类生长素释放肽已在多项针对其他疾病适应症的临床试验中进行了测试，具有出色的安全性。基于我们第一阶段的积极结果，我们假设人类生长素释放肽可以被开发为急性辐射损伤的有效暴露后缓解剂。在本提案中，我们将使用辐射损伤小鼠模型来鉴定人生长素释放肽的剂量修改因子（DMF）来治疗GI-ARS和造血ARS（H-ARS）。我们还将研究人类生长素释放肽减轻造血和胃肠道损伤的作用。此外，我们还将在非人类灵长类动物（NHP）中进行探索性研究，以评估人类生长素释放肽治疗对胃肠道和血液学对辐射暴露反应的影响。这些拟议的研究应该提供关于人生长素释放肽作为主要针对 GI-ARS 的新型辐射 MCM 的功效的重要信息。我们的最终目标是获得 FDA 批准，使用人生长素释放肽作为放射紧急情况后急性放射损伤患者的安全有效的治疗方法。