This proposal represents a four-year curriculum and research plan that is designed to provide me with the means to transition to an independent investigator. I am an Assistant Professor in Pediatrics in the Division of Critical Care Medicine at Cincinnati Children's Hospital Medical Center with training in molecular epidemiology and sepsis-related basic science research. This application provides a proposed curriculum in epidemiology and immunology and a description of the proposed research project. Sepsis is a clinical entity that involves a massive systemic inflammatory response and can lead to multiple organ dysfunction and death. Systemic physiologic changes lead to endothelial injury, cellular damage and organ failure. The nuclear receptor, peroxisome proliferator-activated receptor-g (PPARg), is involved in the regulation of the inflammatory response in experimental models of sepsis but little is known about the effects in children. Our preliminary data suggest that PPARg is altered in experimental animal models and in critically ill children with sepsis. Furthermore we have demonstrated that diet is also an important factor of sepsis susceptibility in animal models. The central hypothesis of the application is that the PPARg pathway is altered in patients with sepsis and that diet further affects the inflammatory response to sepsis in a PPARg-dependent manner. This hypothesis will be tested by pursuing three specific aims: 1) Determine the alterations in the PPARg pathway in monocytes from children with sepsis;2) Determine the therapeutic efficacy of PPARg ligands in the inflammatory response in ex vivo monocytes from children with septic shock;3) Determine the role of PPARg in the increased susceptibility to sepsis in obesity.
Under aim 1 we will utilize a clinical approach to investigate alterations in PPARg in peripheral blood monocytes from children with sepsis.
Aim 2 will use a translational approach using ex vivo monocytes to investigate the therapeutic efficacy of PPARg ligands in altering the inflammatory response in sepsis.
Aim 3 will use a basic science approach where in vivo and in vitro studies will be used to determine the role of PPARg in the increased susceptibility to sepsis in obesity. The proposed research is significant because it can lead to novel therapies for patients with sepsis, including the potential use of FDA-approved PPARg ligands, thiazolidinediones, which can augment the PPARg pathway.
The results of this investigation will provide useful information in developing new therapies to target the imbalance which occurs in children with sepsis. Furthermore, it will provide an understanding of the increased inflammatory state associated with obesity and of the increased susceptibility of obese patients to worse outcomes during critical illness.
|Sherwin, Catherine M T; Ding, Lili; Kaplan, Jennifer et al. (2011) Optimal study design for pioglitazone in septic pediatric patients. J Pharmacokinet Pharmacodyn 38:433-47|
|Kaplan, Jennifer M; Hake, Paul W; Denenberg, Alvin et al. (2010) Phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 Is associated with the downregulation of peroxisome proliferator-activated receptor (PPAR)-ýý during polymicrobial sepsis. Mol Med 16:491-7|