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

描述（由申请人提供）：我们的提案的最终目标是开发一种新的治疗方法，将挽救老年脓毒症患者的生命。败血症是非心脏重症监护病房（ICU）中最常见的死亡原因。这在老年人中是一个特别严重的问题。老年人（65岁）占美国人口的12%，但占败血症病例的65%。近80%的感染性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（GH）促分泌素受体1a（GHSR 1a，即，生长激素释放肽受体）。我们已经证明，胃饥饿素的管理抑制炎症反应，减轻器官损伤，并降低死亡率在年轻的败血症动物。生长激素释放肽的有益作用归因于通过脑中的生长激素释放肽受体激活迷走神经。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治疗未能挽救老年脓毒症动物。年龄相关性炎症与中枢对ghrelin的低反应性有关，这导致大脑背侧迷走神经复合体（DVC）中的副交感神经刺激神经元活动减少。Ghrelin受体的下调是中枢低反应性的原因。最近，我们发现低剂量的大鼠生长激素处理上调老年大鼠的生长激素释放肽受体。在人类中，GH水平在25岁后每十年下降约15%。我们已经证明，在老年脓毒症动物中，用大鼠生长激素释放肽与大鼠GH组合治疗可减少炎症并减轻组织损伤。然而，考虑到将大鼠蛋白应用于人体的潜在免疫原性，需要开发来源于人的ghrelin/GH作为脓毒症患者的治疗剂。因此，将在本提案中检测人ghrelin/GH。此外，将使用盲肠结扎和穿孔（CLP）诱导的脓毒症的临床相关性更高的模型来确定人生长激素释放肽/GH在老年动物中的作用。该项目的主要目的是证明进一步开发和商业化人生长激素释放肽与人GH联合作为老年人群脓毒症的新型治疗方法的可行性。我们计划首先确定人GH作为老年大鼠中生长素释放肽致敏剂的最佳剂量，然后评估人生长素释放肽/GH对老年脓毒症大鼠中炎症反应和组织损伤的剂量依赖性作用，最后确定人生长素释放肽与人GH组合对老年大鼠中脓毒症诱导的死亡率的作用。我们未来的目标（SBIR II期及以后）是获得商业利用的人ghrelin/GH作为一种安全有效的治疗老年患者患有脓毒症。

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.