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.
Sepsis is a common disorder affecting nearly 750,000 people annually in the United States. Despite the advanced theories regarding its pathogenesis, there has been no major breakthrough in treatment. Sepsis is particularly a serious problem in the geriatric population since elderly patients with sepsis have much higher morbidity and mortality rates. Although this problem is increasingly recognized, current treatment options for aged septic patients are very limited. Recently, the only FDA-approved drug for sepsis, activated protein C (Xigris(R), marketed by Eli Lilly), has been voluntarily withdrawn from the market because of the lack of sustained survival benefits. Thus, successful development of an effective anti-sepsis therapy for the geriatric population will not only have a positive impact on health care, but will also have significant commercial benefits.