PRECLINICAL TESTING OF HUMAN GHRELIN AND GROWTH HORMONE FOR SEPSIS IN THE ELDLY

描述(由申请人提供)：我们建议的最终目标是开发一种新的治疗方法，以挽救老年脓毒症患者的生命。脓毒症是非心脏重症监护病房(ICU)最常见的死亡原因。在老年人口中，这是一个特别严重的问题。老年人(即65岁)占美国人口的12%，但占败血症病例的65%。近80%的败血症死亡发生在老年患者中。虽然这个问题越来越被认识到，但目前老年脓毒症患者的治疗选择非常有限。Ghrelin是生长激素促分泌素受体1a(GHSR1a，即Ghrelin受体)的内源性配体。我们已经证明，在幼年败血症动物中，给予Ghrelin可以抑制炎症反应，减轻器官损伤，并降低死亡率。Ghrelin的有益作用归因于通过大脑中的Ghrelin受体激活迷走神经。我们还发现，在内毒素血症下，老年大鼠比年轻大鼠产生更多的促炎细胞因子，而Ghrelin治疗未能挽救老年败血症动物。年龄相关性炎症与中枢对Ghrelin的低反应性有关，Ghrelin导致大脑背侧迷走神经复合体(DVC)的副交感神经刺激性神经元活动减少。Ghrelin受体的下调是中枢性低反应的原因。最近，我们发现小剂量的GH治疗可以上调老年大鼠Ghrelin受体的表达。在人类中，生长激素水平在25岁以后每十年下降约15%。我们已经证明，用大鼠生长激素和大鼠生长激素联合治疗可以减轻老年脓毒症动物的炎症和组织损伤。然而，考虑到将大鼠蛋白应用于人类具有潜在的免疫原性，败血症患者需要开发来自人的Ghrelin/GH作为治疗药物。因此，人类Ghrelin/GH将在该提案中进行测试。此外，将使用更具临床相关性的盲肠结扎和穿孔(CLP)引起的脓毒症模型来确定人Ghrelin/GH对老年动物的影响。这个项目的主要目标是证明进一步开发和商业化人类生长激素与人生长激素联合作为老年人群脓毒症的新疗法的可行性。我们计划首先确定人GH作为老年大鼠Ghrelin增敏剂的最佳剂量，然后评估人Ghrelin/GH对老年脓毒症大鼠炎症反应和组织损伤的剂量依赖效应，最后确定人GH与人GH联合应用对老年大鼠脓毒症死亡的影响。我们未来的目标(SBIR第二阶段及以后)是将人类Ghrelin/GH作为一种安全有效的治疗老年脓毒症患者的方法获得商业化应用。

DESCRIPTION (provided by applicant): The ultimate goal of our proposal is to develop a novel therapeutic approach that will save lives of aged septic patients. Sepsis is the most common cause of death in the non-cardiac intensive care units (ICU). It is particularly a serious problem in the geriatric population. The elderly (e 65 years of age) accounts for 12% of the US population but 65% of sepsis cases. Nearly 80% of septic deaths occur in elderly patients. Although this problem is increasingly recognized, current treatment options for aged septic patients are very limited. Ghrelin is an endogenous ligand for the growth hormone (GH) secretagogue receptor 1a (GHSR1a, i.e., ghrelin receptor). We have shown that administration of ghrelin inhibits inflammatory responses, attenuates organ injury, and reduces mortality in young septic animals. Ghrelin's beneficial effects are attributed to the activation of the vagus nerve through ghrelin receptors in the brain. We have also shown a greater production of proinflammatory cytokines in aged than young rats under endotoxemia, and ghrelin treatment fails to rescue aged septic animals. The age-related hyperinflammation is associated with central hyporesponsiveness to ghrelin, which results in reduction of parasympathostimulatory neuronal activity in the dorsal vagal complex (DVC) of the brain. Down regulation of ghrelin receptor is responsible for central hyporesponsiveness. Recently, we have discovered that a low dose treatment of rat GH up regulates the ghrelin receptor in aged rats. In humans, GH levels decline ~15% per decade after age 25. We have demonstrated that treatment with rat ghrelin in combination with rat GH reduces inflammation and attenuates tissue injury in aged septic animals. However, in consideration of the potential immunogenicity of applying rat proteins in humans, development of ghrelin/GH derived from human as therapeutic agents is needed for septic patients. Thus, human ghrelin/GH will be tested in this proposal. Moreover, a more clinically relevant model of sepsis induced by cecal ligation and puncture (CLP) will be used to determine the effect of human ghrelin/GH in aged animals. The primary objective of this project is targeted towards demonstrating the feasibility of the further development and commercialization of human ghrelin in combination with human GH as a novel therapy for sepsis in the geriatric population. We plan to first determine the optimal dosage of human GH as a ghrelin sensitizing agent in aged rats, and then assess the dose-dependent effect of human ghrelin/GH on inflammatory responses and tissue injury in aged septic rats, and finally determine the effect of human ghrelin in combination with human GH on sepsis- induced mortality in aged rats. Our future goal (SBIR Phase II and beyond) is to obtain commercial utilization of human ghrelin/GH as a safe and effective therapy for aged patients suffering from sepsis.