This proposal presents a five-year research career development program focused on the study of the hepatic response in advanced age after burn injury. Dr. Juan-Pablo Idrovo PI in this project is currently an assistant professor of surgery and critical care at the University of Colorado Denver. The proposed experiments and didactic work will position the Dr. Idrovo with a unique set of cross-disciplinary skills that will facilitate his transition to independence as a surgeon-scientist in hepatic immunology and cell death signaling after burn injury in aged population. With the knowledge gained from the current studies, he plans to develop clinical trials that will apply early interventions and improve outcomes for these patients. Elderly burn patients exhibit higher mortality rates when compared to adult subjects. Given that the role of the liver is to maintain homeostasis under basal and stress conditions, damage to this critical organ is likely to cause the amplified mortality rates in the aged, post-burn. Preliminary data, indicating liver damage, cell necrosis, p38-mitogen-activated-protein- kinase phosphorylation, elevated pro-inflammatory cytokines, RIPK3 and apoptosis genes upregulation in aged mice post-burn as compared to their younger counterparts, allowed Dr. Idrovo to hypothesize that p38- signaling is amplified in Kupffer cells, which triggers cytokine production, thus inducing hepatocyte necroptosis and apoptosis. Dr. Idrovo's proposed focus is to determine the amount of p38-Kupffer-cell-induced inflammation of the liver and to examine hepatocyte cell-death mechanisms from young versus aged mice, following burn injury. Data obtained may prompt new inquiries that relate to aged burn victims globally. More specifically, the aims of this proposal are: 1) To determine the role of p38 activation in Kupffer cell-induced liver inflammation after burn injury in young and aged mice, and 2) To examine the cell death signaling (RIPK3 dependent necroptosis and FAS/FasL apoptosis) in the post-burn hepatic response in young and aged mice. The career development plan outlined in this proposal includes a mentorship team led by Dr. Elizabeth Kovacs and Dr. Aik C. Tan along with a scholarship oversight committee that includes Drs. Weng-Lang Yang, Anne Wagner (Director of the Burn Center) and Robert Mcintyre Jr. (Chief of Trauma/Critical Care). The training and mentorship proposed in this application is specifically designed to strengthen and improve Dr. Idrovo's knowledge on death signaling pathways in the liver, as well as clinical trials designed to ensure success in his ultimate career goals. To facilitate this, a reduction in his clinical and educational responsibilities is proposed to provide him with 75% protected research time. Dr. Idrovo has access to excellent research facilities and equipment to complete all proposed studies. With these changes in protected time, along with the complete support of his Department Chair and Section Chief, he will have adequate time and mentorship to successfully complete the proposed studies, follow through with his career development plan and effectively align himself to launch his career as an independent scientist.
Increased elderly mortality after burn injury, relative to young, is a major health problem in which liver failure has been found to be a common denominator. Heightened hepatic inflammation, as well as increased hepatocyte cell death, seen in aged mice subjected to scald injury, pointed us to interrogate liver macrophages, cytokine production, and modes of hepatocyte cell death (apoptosis and necroptosis). Identifying mechanisms involved in this abnormal cytokine release and hepatocyte cell death in aged animals, will enable us to develop drugs targeting these pathways and improve the outcome for elderly burn victims.
