This is a Program Project to investigate the basic regulatory mechanisms of colonic motility. Initial observations from the Program Director's laboratory have described the diversity of electrical and mechanical behavior through the muscularis of the canine colon. Experiments proposed in this application will investigate the basis for electrical and mechanical heterogeneity in the colon. The thread of the Program runs from neural organization and regulation of electrical and mechanical activity to molecular regulation of contractile proteins. Project 1 will investigate neural control of specific regions of the muscularis and attempt to determine the organization of intrinsic and extrinsic inputs. Project 2 will study the source and propagation of myogenic electrical activity and attempt to isolate the cell-type responsible for pacemaker activity. Project 3 will study the ionic currents underlying electrical activity and the regulation of these currents by agonists and second messengers. Project 4 will study Ca-activated K channels. Preliminary data suggests that these channels may be an important site of action for neurotransmitters. Project 5 will study receptor distribution through the muscularis and the coupling of receptors to responses. Results will provide information about 2nd messenger mobilization. Project 6 will study the source and dynamics of Ca 2+ signaling. State-of-the-art fluorescence measurements will allow real-time monitoring of [Ca2+]i during spontaneous electrical activity and agonist-evoked responses. Project 7 will investigate molecular regulation of contraction. Studies will correlate protein phosphorylation with the development of force and determine which proteins serve as regulators of contraction. This is a unique Program Project because most of the Principal Investigators have just recently become involved in studies of colonic smooth muscle. In effect this Program Project will recruit several talented investigators into the field of gastrointestinal motility. Fresh ideas and rigorous, state-of-the-art research tools will be brought together into a focused investigation of the basic functions of colonic muscle. The broad knowledge of the Principal Investigators about excitable and contractile cells will greatly enrich our knowledge about colonic motility.
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