The long-term goals of this study are to define the changes in ion channel activity in colonic inflammation. Ulcerative colitis is an inflammatory bowel disease characterized by recurrent episodes of colonic inflammation and tissue degeneration. The main hypothesis to be tested is that inflammation induces specific changes in ion channels within the circular smooth muscle cells resulting in decreased cell excitability and contraction. Preliminary data demonstrate down-regulation of L-type calcium currents and an up-regulation of the ATP-sensitive potassium channels in the murine colonic smooth muscle myocytes from the dextran sulphate -sodium (DSS) model of experimental colitis.
Specific Aim 1 is to define the cellular basis of altered calcium channel function in the DSS -treated mice colon. In this aim, we will determine the changes in the biophysical properties, protein and gene expression and regulation by tyrosine kinase of the calcium channels with inflammation. We will also define the minimal binding domain for c-src kinase on the carboxy-terminus of the calcium channel.
In specific aim, 2 we will determine the mechanisms associated with the enhanced activity of the ATP-sensitive potassium channel. We will identify the isoforms comprising this channel and define the changes in isoform expression levels with inflammation.
Specific Aim 3 is to determine the functional effects of altered ion channel activity in whole tissue segments.
This aim will integrate the findings of single channel modulation on whole tissue function following inflammation. Preliminary data indicate that enhanced sensitivity to the potassium channel openers observed in single channel studies correlate with increased hyperpolarization of whole tissue segments of colonic smooth muscle. The information obtained from these studies will increase our understanding of the potential changes in ion channel activity with inflammation and help identify novel therapeutic agents in the treatment of motility disturbances in the pathophysiology of the colon.
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