Background and Significance

Filling the Knowledge
Gaps in Burns

P50 Programs in Injury

Copyright © 2004-2013 Massachusetts General Hospital

The Burn Research Center at the Massachusetts General Hospital serves as the focal point within MGH for research on burn injury. As the first-in-the-nation P50 award (GM-21700) from the National Institute of General Medical Sciences, the MGH Center has sought to advance our understanding of post-burn injury alterations of metabolic patterns and nutritional requirements from immediately after injury through recovery. Since its first year of funding in 1974, the Center has successfully integrated basic laboratory observations and principles into the clinical setting and has fostered multidisciplinary interactions within the MGH research and clinical communities and beyond. In association with the Center, there has been a NIGMS T32 Burn Research Training Grant (GM-07035) funded since 1975, which currently has three positions available for postdoctoral training in burn and trauma research.

Through the years, the studies from the Center grant have contributed novel insights into our understanding of the metabolic dysregulation that occurs in response to burn injury, in large part from the interactive and synergistic nature of the projects and cores. The Center has recruited and retained a truly outstanding multidisciplinary investigative team of scientists and clinicians that is collectively much stronger than the sum of its parts.

In the new Center re-funded on June 1, 2013, we are taking advantage of very new genomic data and its analyses, and computational biology methods from the NIGMS-funded Glue Grant Program, “Inflammation and the Host Response to Injury” to study the innate inflammatory response postburn injury and its influence upon metabolism. This will be accomplished with the addition of the Stanford Genome Technology Center and Children’s Hospital-Boston as new participating sites to complement the existing rich environment of MGH. We have expanded our “team science” relationships with the SGTC and CH that already exist to create a new blend of academic expertise for sharing genomics and computational resources and ideas across geographical campuses.

The Projects and Cores

To date, investigators, including our own, have focused on single molecules or individual pathways with excellent, but limited, impact upon hypermetabolism, hyperglycemia, catabolism, a shift from carbohydrate to fatty acid oxidation, and muscle wasting. Many of the research methods and interventions studied, including stable isotope steady-state kinetics, nutrient supplementation, and anabolic agent administration yielded important, but limited improvements. The new Center takes into account, in addition to its primarily traditional approaches, new systematic genome-wide technologies to understand the global impact of burn injury on metabolism. Rather than looking at single molecules or pathways, with the successful completion of our projects, new mechanistic-based therapies to enhance skeletal muscle insulin sensitivity might promote an anabolic state, restoring nutrient flux to a level compatible with an optimal and uncomplicated recovery from burn injury. The projects can be summarized in the following statements.

Project 1 applies physiologic, pharmacologic, and genomic approaches to critically analyze the in vivo putative pathways that lead to decreased protein anabolism, enhanced catabolism, and apoptosis in muscle resulting in muscle wasting and test several pharmacological interventions to reverse the signaling aberrations. (Molecular Mechanisms of Muscle Wasting - Project 1)

Project 2 applies physiologic, pharmacologic, and genomic approaches to investigate mitochondrial reactive oxygen species (ROS) in oxidative stress induced after major injury and the potential for a novel SS peptide antioxidant (SS31) to reduce this oxidative stress by scavenging ROS, thereby correcting the burn-induced alterations in mitochondrial function. (Drug Therapy to Ameliorate Mitochondrial Dysfunction - Project 2)

Project 3 applies physiologic approaches to identify, and experimentally disrupt, the mechanisms of insulin resistance and skeletal muscle catabolism following burn injury by determining whether IRS-protein loss or phosphorylation of candidate S/T-sites dysregulates insulin signaling after burn injury. (Molecular Mechanisms in Burn-Induced Muscle Insulin Resistance in Genetic Models - Project 3)

Project 4 applies physiologic, pharmacologic, and genomic approaches to determine the role of the IRS1/PTP- 1B/Akt/FoxOs) pathway and whether the FoxOs play a critical role in burn injury-induced insulin resistance and related metabolic derangements in skeletal muscle after burn injury. (Molecular Mechanisms in Burn-Induced Insulin Resistance in Humans - Project 4)

In support of the four research projects, several core resources and facilities have been established to provide the cornerstones to the projects. The Administration Core is the primary hub for all research activities of the Center and coordinates all administrative, educational, budgetary and informational activities of the Center. The Human Studies Research Core serves as the tool to maintain the clinical infrastructure for reliable sample and data collection and analysis and for the coordination of the various human studies. The PET and Mass Spectroscopy Facility provide the Center with the capability to study clinical phenomena at the tissue, cellular and genetic levels, non-invasively with Positron Emission Tomography. (PET) is becoming increasingly important as a fundamental tool in biology that provides high-resolution anatomical and molecular imaging. The Computational Genomics Core provides the Center with the capability to conduct genome-wide bioinformatic, statistical and pathway analyses of the studies and develop an injury-specific knowledgebase of the genomic, proteomic, and metabolic response to burn injury for subsequent disease modeling and target prediction as well as data warehousing and data sharing.