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

基本信息

批准号：
8198739
负责人：
Weng-Lang Yang
金额：
$ 29.78万
依托单位：
THERASOURCE, LLC
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-20 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8198739
关键词：
Acute Adult Aftercare Animals Apoptosis Area Under Curve Attenuated Autopsy Blood Coagulation Disorders Blood Platelets Body Weight Cleaved cell Clinical Trials Coagulation Process Complete Blood Count Creatinine Data Development Devices Disease Dose Drug Kinetics Early treatment Enzymes Erythrocytes Functional disorder Future GHS-R1a Goals HMGB Proteins Half-Life Heart Hematoxylin and Eosin Staining Method Inflammatory Response Injury Interleukin-6 Ionizing radiation Kidney Label Leukocytes Ligands Liver Lung Measurement Measures Mediating Medical Monitor Neuraxis Nuclear Patients Peptides Peripheral Pharmaceutical Preparations Phase Physiological Plasma Property Public Health Radiation Radiation Injuries Radiation Syndromes Rattus Reporting Risk Serum Small Business Innovation Research Grant Small Intestines Somatotropin Spleen Staining method Stains TNF gene TdT-Mediated dUTP Nick End Labeling Assay Terrorism Testing Therapeutic Time Tissues Western Blotting Whole-Body Irradiation caspase-3 clinically relevant commercialization cytokine dosage drug clearance gastrointestinal ghrelin ghrelin receptor human ghrelin improved irradiation male mortality novel phase 2 study preclinical study response weapons

项目摘要

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.

描述（由申请人提供）：该 SBIR 第一阶段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件以及恐怖辐射暴露场景中。急性放射综合症是在全身或部分身体受到高剂量放射线照射后出现的。尽管我们对急性放射损伤病理生理学的理解取得了进展，但急性放射综合征的治疗主要是支持性的。关于急性放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的有效新型缓解剂存在迫切的未满足的医疗需求。 Ghrelin 是一种胃肠道肽，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。最初报道胃饥饿素通过刺激中枢神经系统中的胃饥饿素受体来诱导生长激素释放。大量证据表明生长素释放肽的其他生理特性是由中枢和外周生长素释放肽受体介导的。尽管人类生长素释放肽已被证明对某些疾病有益，但这种肽是否可以减轻急性辐射综合症仍不清楚。为了研究这一点，成年雄性大鼠接受 10 Gy 全身照射 (TBI)。我们的初步数据表明，TBI 后 6 小时施用人生长素释放肽（即非常早期的治疗）可降低死亡率。然而，延迟施用人生长素释放肽（临床意义更大）是否也能降低 TBI 引起的死亡率仍不清楚。因此，我们假设 TBI 后延迟施用人生长素释放肽可减轻组织损伤并提高生存率。该 SBIR 第一阶段项目的主要目标是证明人类生长素释放肽作为有效缓解剂（辐射后 24 小时或更晚）的开发和商业化的可行性，以降低急性辐射暴露场景后的大规模死亡率。人生长素释放肽（延迟治疗）的最佳剂量将通过评估以下因素来确定： 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 引起的死亡率的剂量反应效应和时程； 3) 人生长素释放肽在健康和受辐射动物中的药代动力学。我们的最终目标（SBIR II 期及以后）是获得人类生长素释放肽的商业利用，作为急性辐射损伤患者的安全有效的缓解剂。公共卫生相关性：2001 年 9 月 11 日恐怖袭击发生后，滥用电离辐射或核装置作为恐怖主义武器已被认为是重大的公共卫生威胁。尽管我们对急性放射损伤病理生理学的理解取得了进展，但急性放射综合征的治疗主要是支持性的。关于放射损伤的具体治疗方法的信息非常少。因此，对于急性辐射损伤患者而言，迫切需要一种新型且有效的缓解剂，但尚未得到满足。