Grant: $156,000 - National Institutes of Health - Jul. 14, 2009
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Award Description: The parent grant for this Administrative Supplement investigates the effects of ethanol on excitation-contraction (E C) coupling, using animal models and isolated cell systems. Our work to date has shown that both acute and chronic ethanol exposure have direct effects to suppress the cytosolic Ca2+ ([Ca2+]c) transients responsible for EC-coupling, and that this is mediated largely by alterations in plasma membrane and sarcoplasmic reticulum Ca2+ channel function. One aspect of the adaptation in E-C coupling in response to chronic ethanol consumption is a reduced ability of ?-adrenergic activation to enhance the rate and amplitude of [Ca2+]c increase. This is associated with reduced responsiveness of the L-type Ca2+ channel, despite a paradoxical increase in total channel protein expressed by cardiomyocytes from ethanol-fed rats. This has led us to hypothesize there may be alterations in the targeting of cAMP signaling to the L-type Ca2+ channel, and/or, that the subunit composition of the channel may be altered. We have also discovered that chronic ethanol feeding leads to an upregulation of the mitochondrial uncoupling protein UCP2, which is likely an adaptation to protect against oxidative stress. However, elevated levels of UCP2 also have deleterious effects on E-C coupling, because reduced mitochondrial function removes an important regulatory control of the Ca2+-induced Ca2+ release process at the dyadic junction. The two aims of this supplement are (1) to complete studies of cAMP signaling and L-type Ca2+ channel subunit composition in our models of chronic ethanol consumption, and (2) to follow up on our new findings indicating that upregulation of UCP2 interferes with normal regulation of Ca2+ release. These studies utilize cell and molecular biology approaches, together with imaging of [Ca2+]c and molecular biosensors of cAMP, all techniques that are well established in the laboratory. The funding requested in this supplemental application has allowed the retention of two research staff in the laboratory, a technician and a postdoctoral fellow, and also provides research support for a second postdoctoral fellow. During the first few months of support, we have made significant progress on studies of UCP2 and modifications of cAMP signaling in chronic alcohol consumption. These advances will enhance the competitiveness of this project for full renewal. In particular, we have submitted for publication an initial manuscript on the effects of UCP2 expression in neonatal cardiomyocytes (currently in review at Circulation Research), and are finalizing a manuscript on the effects of chronic ethanol consumption on cardiac E-C coupling.
Project Description: As defined in the Award Description field.
Jobs Summary: a) 1 research technician, 2 postdoctoral fellows. b) The ARRA supplement is providing direct salary support for 1 research technician and 1 postdoctoral fellow. These individuals were previously supported on the parent grant, and would have had to be laid off without the ARRA supplemental funding. In addition, the research support under the ARRA supplement has allowed an additional postdoctoral fellow to make progress, and has therefore contributed to the continuation of that individual's employment (Total jobs reported: 3)
Project Status: Less Than 50% Completed
This award's data was last updated on Jul. 14, 2009. Help expand these official descriptions using the wiki below.