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Diverse physiological conditions such as burn
injury, cancer, AIDS lead to a hypercatabolic
state marked by the loss of proteins, primarily
derived from skeletal muscle. The sustained loss
of proteins results in loss of muscle mass and
strength, poor healing, and long-term
hospitalization. These problems are further
compounded by the deterioration of immunity to
infection which is a leading cause of morbidity
and mortality of traumatic patients.
Investigation reveals an imbalance in the
skeletal muscle protein-amino acid equilibrium
as the cause for the loss of nitrogen from the
body via urinary excretion. Such muscle wasting
results in a number of secondary complications
including prolonged ventilator dependence,
increased incidence of pneumonia, and prolonged
physical rehabilitation. In addition, severe
trauma is also frequently associated with immune
dysfunction; infection, and subsequent
multi-organ dysfunction syndrome are the leading
cause of morbidity and mortality following
trauma. Treatment to ameliorate muscle wasting
and immune dysfunction, including proteolytic
inhibitors and cytokine-based therapies have yet
to prove efficacious. To achieve therapeutic
efficacy may require a better understanding of
the early events after onset of injury. |
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The overall goal of this project is on two
aspects a) better mechanistic understanding on
the cause of muscle wasting and immune
dysfunction and b) development of novel
therapies. Since muscle wasting occurs at sites
distant from trauma, the implication is that
circulating trauma-induced proteolysis-inducing
factor(s) must exist. Previously, PI showed that
Interferon-g protein modulates hypercatabolism
in skeletal muscle and immune cells, and a low
dose of insulin is an effective prophylactic
therapy. Further, exogenous insulin
supplementation in rat model has shown
beneficial effects. Based on these
findings, one of the projects currently pursued
is evaluating the potential role of Interleukin
-18 in traumatic injury. |
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