Radiation Combined Injury: Mechanisms and Therapeutic Approaches

描述(申请人提供)：在恐怖分子辐射暴露的情况下，辐射受害者可能遭受其他伤害，如感染和败血症。尽管我们对辐射损伤的认识有了进步，败血症患者的治疗也取得了进展，但关于辐射复合损伤(例如，辐射暴露后感染和脓毒症)的信息很少。在我们的初步研究中，我们已经表明，辐射复合损伤会导致组织损伤、促炎细胞因子上调和细胞凋亡。辐射复合损伤减少了一种新的“肠-脑”肽Ghrelin的产生，并增加了交感神经的活性。我们发现，辐射复合伤后给予大鼠胃促生长素可产生多种有益效果。Ghrelin是一种由28个氨基酸组成的多肽，在人和大鼠体内有两种不同的氨基酸。Ghrelin抑制交感神经系统，表现为脓毒症时脑内去甲肾上腺素(NE)释放减少和交感刺激神经元失活。一种特定的Ghrelin受体拮抗剂增加了正常动物体内去甲肾上腺素和肿瘤坏死因子-a的产生，并恶化了败血症引起的死亡。Ghrelin在脓毒症中的作用也涉及副交感神经系统，因为迷走神经切断术阻止了它的有益效果。尽管在辐射复合损伤后给予大鼠胃促生长素是有保护作用的，但人类胃促生长素是否也是有益的仍不清楚。阻碍Ghrelin作为治疗剂发展的一个障碍是大鼠肽对人类的潜在免疫原性。因此，我们假设给予人Ghrelin可以减轻组织损伤和炎症，并降低辐射复合损伤后的死亡率。我们进一步假设，人类Ghrelin的有益作用是由其交感神经抑制和副交感神经刺激特性介导的。因此，R21/R33项目的目标是完成人类Ghrelin作为一种新型治疗药物在降低辐射复合伤后死亡率方面的临床前开发，并确定其有益作用的机制。在R21阶段，我们将1)确定人类Ghrelin是否减轻组织损伤和炎症；2)评估人类Ghrelin是否提高存活率；3)进行可行性实验，展示人类Ghrelin对辐射复合损伤后自主神经系统的影响。在R33阶段，我们将4)深入研究人类Ghrelin的有益作用机制；5)确定人Ghrelin对细胞凋亡、心血管反应、组织损伤和促炎细胞因子的量效效应，以及对辐射复合损伤后存活的剂量和时间效应；6)评估人Ghrelin在正常动物和损伤动物中的毒性和药代动力学特性。这些拟议的研究应该提供有用的机制和临床前信息，使我们能够向FDA提交IND申请，以启动临床试验，以便进一步开发人Ghrelin作为一种安全有效的治疗方法，用于治疗辐射暴露以及随后的感染和败血症。与公共健康相关的声明：在恐怖分子辐射暴露的情况下，辐射受害者可能遭受其他伤害，如感染和败血症。最初的辐射损伤后的感染和败血症会显著增加死亡率。然而，关于辐射复合损伤(即辐射暴露后感染和败血症)的信息很少。显然，对于辐射复合伤的受害者，迫切需要一种有效和新颖的治疗方法，这一需求尚未得到满足。在这个项目中，我们提出了一种创新的方法来开发一种治疗放射复合损伤的新药。

DESCRIPTION (provided by applicant): In the terrorist radiation exposure scenario, radiation victims likely suffer from additional injuries such as infection and sepsis. Despite advances in our understanding of radiation injury or advances in the management of sepsis patients, little information is available regarding radiation combined injury (e.g. radiation exposure followed by infection and sepsis). In our preliminary studies, we have shown that radiation combined injury causes tissue damage, proinflammatory cytokine upregulation, and apoptosis. Radiation combined injury decreases the production of a novel "gut-brain" peptide ghrelin and increases the sympathetic activity. We discovered that administration of rat ghrelin after radiation combined injury produces various beneficial effects. Ghrelin is a 28-amino acid peptide in both humans and rats with difference in two amino acids. Ghrelin inhibits the sympathetic nervous system, as evidenced by the reduction of norepinephrine (NE) release and inactivation of sympathostimulatory neurons in the brain in sepsis. A specific ghrelin receptor antagonist increases norepinephrine and TNF-a production in normal animals and worsens sepsis-induced mortality. The action of ghrelin in sepsis also involves the parasympathetic nervous system, as vagotomy prevents its beneficial effects. Although administration of rat ghrelin after radiation combined injury is protective, it remains unknown whether human ghrelin is also beneficial. An obstacle hampering development of ghrelin as a therapeutic agent is the potential immunogenicity of rat peptides in humans. We therefore hypothesize that administration of human ghrelin attenuates tissue damage and inflammation, and reduces mortality after radiation combined injury. We further hypothesize that the beneficial effect of human ghrelin is mediated by its sympathoinhibitory and parasympathostimulatory properties. Thus, the goal of this R21/R33 project is to complete the preclinical development of human ghrelin as a novel therapeutic agent in reducing mortality after radiation combined injury and to determine the mechanism responsible for its beneficial effects. In the R21 Phase, we will 1) determine whether human ghrelin attenuates tissue damage and inflammation; 2) assess whether human ghrelin improves survival; and 3) conduct feasibility experiments demonstrating the effect of human ghrelin on the autonomic nervous system after radiation combined injury. In the R33 Phase, we will 4) conduct in-depth studies to delineate the mechanism responsible for human ghrelin's beneficial effects; 5) determine the dose-response effect of human ghrelin on apoptosis, cardiovascular response, tissue damage, and proinflammatory cytokines, as well as its dose- and time-course effect on survival after radiation combined injury; and 6) assess the toxicity and pharmacokinetic properties of human ghrelin in normal and injured animals. These proposed studies should provide useful mechanistic and preclinical information that will allow us to file an IND application to the FDA for initiating clinical trials in order to further develop human ghrelin as a safe and effective therapy for victims with radiation exposure and subsequent infection and sepsis. PUBLIC HEALTH RELEVANCE STATEMENT: In the terrorist radiation exposure scenario, radiation victims likely suffer from additional injuries such as infection and sepsis. Infection and sepsis after the initial radiation injury can significantly increase mortality. However, very little information is available regarding radiation combined injury (i.e., radiation exposure followed by infection and sepsis). It is obvious that there is an urgent unmet medical need for an effective and novel therapy for victims with radiation combined injury. In this project, we propose an innovative approach to develop a new medicine for the treatment of radiation combined injury.