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Role of peroxisome-proliferator activated receptors in sepsis and trauma
We are investigating the role of the nuclear hormone receptors, peroxisome-proliferator activated receptors (PPARs) and liver X receptors (LXRs) in experimental models of sepsis and trauma. We have discovered that these important receptors, which normally control lipid and glucose metabolism, are also beneficial factors in combating infections and inflammation during sepsis and trauma. A major focus of investigation is to understand how these receptors interact with pathways that facilitate the progression of inflammation and cell death, such as the nuclear factor- κΒ and activator protein-1, and ultimately lead to organ damage. Also, we are investigating the molecular mechanisms that control the function of these receptors, such as the recruitment of ligands, co-activators and co-repressors.
To support the clinical relevance of our data, in collaboration with Kaplan and Wong laboratories we have observed that the expression and function of PPARγ is altered in peripheral blood mononuclear cells and correlates with severity of sepsis in critically ill children. These findings, together with the basic science discoveries, hold the promise to identify new therapeutic targets to treat sepsis and improve child health. Since the synthetic ligands for PPARγ, the thiazolidinediones, are used clinically as anti-diabetic drugs, we are taking further steps to explore the possibility to use this class of compounds in pediatric patients with sepsis and we have started to study safety of pioglitazone treatment in a prospective randomized phase I clinical trial.
The clinical course and outcomes of sepsis and trauma is significantly impacted by the age of the patient. Although the co-morbidity of chronic inflammatory or dysmetabolic diseases, and unhealthy habits contribute to the clinical variability, age appears a risk factor of increased organ dysfunction and mortality in elderly when compared with pediatric patients. Our laboratory is focused in understanding the molecular mechanisms that link the aging process to the enhanced susceptibility to organ damage after infectious or traumatic events. Using experimental models of severe hemorrhage, we have observed that in old rodents there is an excessive inflammatory response that damages vital organs such as lungs, kidney and liver. Our studies have shown that the nuclear hormone receptor PPARγ is an important counter-regulator of the inflammatory response and protects the cells from damage and death. However, we have discovered that the expression and function of PPARγ and other nuclear hormone receptors is diminished as the body ages. We are currently investigating the molecular pathways mediated by the extracellular signal regulated kinases (ERK) that alter the chemical structure of PPARγ. We are also testing different pharmaceutical compounds that may rescue the function of PPARγ even in old organisms. This research will help to design therapeutic interventions, which are specific to the age of the patient.
An inability to use oxygen at the cellular level contributes to the development of organ damage in critically ill patients. Mitochondria use oxygen to provide energy for cellular processes. We are investigating whether dysfunction of these organelles leads to cellular energetic failure and contributes to organ failure and whether this phenomenon is age-dependent. Our laboratory is particularly interested on the molecular mechanisms of autophagy, a process that allows the cell to dispose dysfunctional organelles, and mitochondrial biogenesis, a process that allows the cell to restore functional organelles. With the use of experimental models of sepsis as well as novel pharmacological agents we are investigating the role of the PPARγ co-activator-1α (PGC-1α ) and the AMP activated kinase (AMPK) in a variety of metabolic processes, including energy homeostasis in liver, heart and kidneys. The goal of our project is to develop novel therapeutic strategies to maintain cellular energetic status and promote organ recovery in critical illness.
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