PROJECTS

Project 1:
Molecular Mechanisms of Muscle Wasting


Project 2:
Drug Therapy to Ameliorate Mitochondrial Dysfunction


Project 3:
Molecular Mechanisms in Burn-Induced Muscle Insulin Resistance in Genetic Models


Project 4:
Molecular Mechanisms in Burn-InducedInsulin Resistance in Humans


TECHNOLOGY CORES

PET and MS Facility

Computational Genomics


SUPPORT CORES

Human Studies Research

Administration




























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Despite major advances in the management of burn injury, dysregulated metabolism-including sustained hyperglycemia, lipolysis, and protein catabolism-remains a hurdle to recovery. We believe, while catecholamines, glucocorticoid, and other endocrine alterations may each contribute to the catabolic state, severe and lasting insulin resistance following burn injury leads directly to increased hepatic glucose production and skeletal muscle protein catabolism. Amongst various other factors that might initiate or sustain the pathophysiology of thermal injury-such as reactive oxygen species, nitric oxide, or coagulation and complement cascades-inflammatory cytokines, including IL-1β and IL-6, platelet-activating factor (PAF), and TNFα are thought to also promote insulin resistance through S/T phosphorylation of the insulin receptor substrate proteins (IRS1/2). Although intensive insulin therapy promotes reestablishment of glucose tolerance following traumatic injury, frequent episodes of hypoglycemia and persistent muscle catabolism severely limit any benefits accrued. Thus, it is important to develop new strategies that can reverse the consequences of injury by restoring insulin sensitivity in the treatment of hospitalized patients.

The MGH Burn Trauma Center represents our mechanistic endeavors to better understand the metabolic dysregulation in burn injury. 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 Project and Cores

Our research program is organized into four projects that evaluate postinjury insulin resistance and its metabolic impact in skeletal muscle. Projects 1 and 2 investigate the mitochondrial consequences of insulin resistance while Projects 3 and 4 evaluate the IRS1/2 dysregulation consequences of insulin resistance. The Center also includes other core components in support of the four research projects: PET and Mass Spectroscopy Facility, Computational Genomics, Human Studies Research, and Administration.

Project 1: Molecular mechanisms of muscle wasting after burn injury

Project 1 is designed to determine whether inhibitors/activator for GSK-3β, SIRT1, and farnesyltransferease are novel potential strategies to reverse muscle wasting and metabolic derangements in burn patients.

Project 2: Drug therapy to ameliorate mitochondrial dysfunction

Project 2 is designed to determine whether the potent mitochondrial-targeted ROS scavenger tetra peptide SS31 will biodistribute to the inner membrane of mitochondria and reduce the oxidative stress by scavenging ROS.

Project 3: Molecular mechanisms in burn-induced muscle insulin resistance in genetic models

Project 3 is designed to establish the function of Irs1 and Irs2 in skeletal muscle and the relationship between S/T-phosphorylation of IRS1 and PI 3-kinase after burn injury. The project establishes whether S307Irs1 and S302Irs1 modulates insulin sensitivity after burn injury.

Project 4: Molecular mechanisms in burn-induced insulin resistance in humans

Project 4 is designed to establish whether IRS1-FoxO dysregulation is a key contributor to many if not all of the metabolic derangements of burn injury and that down-regulation and subsequent nuclear exclusion of FoxOs improves or eliminates these effects. The project determines whether FoxO1 PMO is a novel potential strategy to reverse insulin resistance and metabolic derangements in skeletal muscle in burn patients.
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