Grants and Contracts Details
Description
Recent studies indicate that diabetes is associated with an increased incidence of respiratory failure, a
heightened risk of postoperative respiratory complications, and a greater need for prolonged mechanical
ventilation. However, it is not known how diabetes produces these problems. One potential explanation is
that uncontrolled diabetes alters respiratory muscle function, reducing the capacity of the respiratory pump.
The purpose of the present proposal is to examine this issue. Our central hypothesis is that poorly controlled
diabetes induces severe free radical mediated diaphragm dysfunction. We will test this hypothesis in the
following groups of studies. Aim I studies will characterize the effects of uncontrolled diabetes on diaphragm
specific force generation, changes in muscle mass, and diaphragm endurance, testing the hypothesis
diabetes induced alterations in diaphragm performance are related to increases in free radical generation.
Aim 1\studies will interrogate a number of free radical generating pathways in muscle (including the cell
surface NADPH oxidase) and determine which pathways are responsible for increased free radical
generation in the diaphragm in diabetes. Aim III studies will determine if iNOS is upregulated in the
diaphragm in diabetes, and will test the hypothesis that iNOS acts as an upstream modulator of free radical
generation. Aim IV studies will examine several downstream targets of diabetes induced free radical
generation in the diaphragm that are responsible for reductions in diaphragm performance, including
contractile protein alterations, calpain mediated reductions in muscle mass, and alterations in mitochondrial
ATP generating capacity. A variety of physiologic, biochemical, proteomic, fluorogenic, pharmacologic and
genetic techniques will be used to test these hypotheses. Our preliminary data represent the first
demonstration of upregulation of NADPH oxidase subunit proteins in skeletal muscle in any disease
process, and suggest that iNOS regulates NADPH oxidase activity and free radical generation in the
diaphragm in diabetes. These new data should provide important information regarding the pathogenesis of
diabetes induced diaphragm dysfunction, and uncover pathways which could provide novel therapeutic
targets for treatment of respiratory muscle weakness in this condition.
Status | Finished |
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Effective start/end date | 4/1/06 → 3/31/12 |
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