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

人类生长素释放肽和生长激素治疗老年脓毒症的临床前测试

• 批准号: 8714409
• 负责人: Weng-Lang Yang
• 金额: $ 22.49万
• 依托单位: THERASOURCE, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8714409
• 关键词: Accounting; Affect; Age; Age-Years; Animals; Attenuated; Autopsy; Body Weight; Bolus Infusion; Brain; Brain Stem; Cardiovascular system; Cause of Death; Cecum; Cessation of life; Clinical; Clinical Trials; Complex; Continuous Infusion; Creatinine; Development; Disease; Dorsal; Dose; Down-Regulation; Elderly; Endotoxemia; Enzymes; FDA approved; FOS gene; Future; GHS-R1a; Goals; HMGB Proteins; Healthcare; Heart; Hematoxylin and Eosin Staining Method; Human; Human Development; Inflammation; Inflammatory Response; Injection of therapeutic agent; Injury; Intensive Care Units; Interleukin-1; Interleukin-6; Kidney; Ligands; Ligation; Lilly brand of drotrecogin alfa activated; Liver; Lung; Marketing; Measurement; Measures; Modeling; Monitor; Morbidity - disease rate; Necrosis; Neurons; Organ; Pathogenesis; Patients; Perfusion; Pharmaceutical Preparations; Phase; Plasma; Population; Preclinical Testing; Production; Puncture procedure; Rat Protein; Rattus; Sepsis; Serum; Small Business Innovation Research Grant; Small Intestines; Somatotropin; Somatropin; Spleen; Staining method; Stains; TNF gene; Testing; Therapeutic Agents; Tissues; United States; Vagus nerve structure; activated Protein C; age related; aged; clinically relevant; commercialization; cytokine; dosage; effective therapy; ghrelin; ghrelin receptor; human ghrelin; immunogenicity; mortality; normal aging; novel; novel therapeutic intervention; older patient; phase 2 study; pre-clinical; public health relevance; response; septic; theories

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.

描述（由申请人提供）：我们提案的最终目标是开发一种新型的治疗方法，以挽救老年化粪池患者的生命。败血症是非心脏重症监护病房（ICU）中最常见的死亡原因。在老年人群中，这尤其是一个严重的问题。老年人（E 65岁）占美国人口的12％，但占败血症病例的65％。老年患者发生近80％的败血症死亡。尽管这个问题越来越被认识到，但对于化粪池患者来说，当前的治疗选择非常有限。生长素素是一种用于生长激素（GH）促分泌受体1a（GHSR1A，即ghrelin受体）的内源性配体。我们已经表明，生长素释放蛋白的给药抑制炎症反应，减轻器官损伤并降低年轻化脓性动物的死亡率。生长素素的有益作用归因于迷走神经通过大脑中的生长素受体的激活。我们还显示，在内毒素血症下，年龄比幼鼠的促炎细胞因子的产生更大，而生长素治疗未能营救老化的化粪池动物。与年龄相关的高炎症与生长素素的中枢性低下有关，这导致大脑背部迷走神经络合物（DVC）中副跟痛的神经元活性的降低。降低生长素释放蛋白受体的调节是造成中心反应性的原因。最近，我们发现大鼠GH的低剂量治疗可调节老年大鼠的生长素释放蛋白受体。在人类中，GH水平25岁后每十年下降约15％。我们已经证明，与大鼠GH结合使用大鼠生长素蛋白的治疗可减少炎症并减轻衰老的化粪池动物的组织损伤。但是，考虑到在人类中施用大鼠蛋白的潜在免疫原性，因此需要源自人类的生长素蛋白/GH作为化粪池患者的治疗剂。因此，将在该提案中测试人类ghrelin/gh。此外，将使用CECAL连接和穿刺（CLP）引起的更具临床相关的败血症模型来确定人类毛素/GH对老年动物的影响。该项目的主要目标旨在证明人类生长素蛋白与人类GH的进一步开发和商业化的可行性，作为老年人群中败血症的新疗法。我们计划首先确定人类GH作为老年大鼠的生长素蛋白敏化剂的最佳剂量，然后评估人类生长素/GH对衰老的败血性大鼠炎症反应和组织损伤的剂量依赖性作用，并最终确定人类GHREL蛋白与人类GH在SEPIS诱导的诱导的死亡中的效果。我们的未来目标（SBIR第二阶段及以后）是为患有败血症患者的老年患者提供对人类生长素/GH的商业利用。