Radiation Combined Injury: Mechanisms and Therapeutic Approaches

描述（由申请人提供）：在恐怖分子辐射照射的情况下，辐射受害者可能遭受额外的伤害，如感染和败血症。尽管我们对放射损伤的理解或脓毒症患者的管理取得了进展，但关于放射联合损伤（例如，放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，辐射复合损伤导致组织损伤，促炎细胞因子上调，和细胞凋亡。放射复合伤减少了一种新的“肠-脑”肽ghrelin的产生，增加了交感神经活性。我们发现在放射复合伤后给予大鼠ghrelin产生多种有益的作用。Ghrelin是一种由28个氨基酸组成的肽，在人类和大鼠中存在两个氨基酸差异。Ghrelin抑制交感神经系统，如通过脓毒症中脑中去甲肾上腺素（NE）释放的减少和交感神经刺激神经元的失活所证明的。一种特异性生长激素释放肽受体拮抗剂可增加正常动物和脓毒症引起的死亡率中去甲肾上腺素和TNF-α的产生。胃饥饿素在脓毒症中的作用还涉及副交感神经系统，因为迷走神经切断术阻止了其有益作用。尽管在放射复合损伤后给予大鼠生长素释放肽具有保护作用，但人生长素释放肽是否也有益仍不清楚。阻碍生长素释放肽作为治疗剂的发展的障碍是大鼠肽在人体中的潜在免疫原性。因此，我们假设，人类生长激素释放肽的管理减轻组织损伤和炎症，并降低放射复合损伤后的死亡率。我们进一步假设，人类生长激素释放肽的有益作用是通过其交感神经抑制和副交感神经刺激特性介导的。因此，该R21/R33项目的目标是完成人ghrelin作为一种新型治疗剂在降低放射联合损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）确定人生长激素释放肽是否减轻组织损伤和炎症; 2）评估人生长激素释放肽是否改善存活率; 3）进行可行性实验，证明人生长激素释放肽对放射联合损伤后自主神经系统的影响。在R33阶段，我们将4）进行深入研究，以阐明负责人ghrelin的有益作用的机制; 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剂量-反应效应，以及其对放射复合损伤后存活的剂量-和时间-过程效应;和6）评估正常和受伤动物中人生长素释放肽的毒性和药代动力学性质。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，从而进一步开发人生长激素释放肽作为辐射暴露和随后感染和败血症患者的安全有效疗法。公共卫生相关声明：在恐怖分子辐射照射的情况下，辐射受害者可能遭受额外的伤害，如感染和败血症。放射损伤后感染和败血症可显著增加死亡率。然而，关于辐射复合损伤的信息非常少（即，辐射暴露，随后是感染和脓毒症）。很明显，有一个迫切的未满足的医疗需求，为受害者的有效和新的治疗与辐射复合损伤。本课题提出了一种新的治疗放射复合伤的药物。

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.