This Program Project will investigate the basic regulatory mechanisms of colonic motility. Experiments will investigate why electrical and mechanical activities differ in circular and longitudinal muscles and how agonists elicit the contractile responses that are fundamental to colonic motility. The Program features cellular and molecular investigations into the origin of pacemaker activity, the mechanisms of electrical excitability, the regulation of electrical and contractile activity by agonists, and the factors that regulate force production. Project 1 will investigate the cellular properties of interstitial cells of Cajal. These cells are thought to be pacemaker cells in the GI tract and to have an important role in neurotransmission. Project 2 will study the characteristics of delayed rectifier K channels. Experiments will determine how unitary conductances participate in currents generated by cells and whether the channels are physiologically regulated. The behavior of delayed rectifier channels will be related to the electrical activity of intact muscles. Project 3 will study the diversity of K channels expressed in smooth muscle and interstitial cells. K channel cDNAs will be isolated, cloned, and expressed in heterologous expression systems in which the properties of specific K channels can be characterized in the absence of contaminating currents. Project 4 will characterize the expression and properties of receptors to putative neurotransmitter substances and study the second messenger coupling that links receptors to cellular effectors. Project 5 will study Ca2+ handling by smooth muscle cells. Mechanisms of cytoplasmic Ca2+ accumulation and clearance will be investigated, and the relationship between intracellular Ca2+ and force production will be characterized. Project 6 will study the molecular mechanisms of force generation. Thin and thick filament regulatory pathways will be investigated. These projects will be supported by an administrative core (Core A), and two core laboratory facilities. Core B will provide tissues and oocytes, prepare isolated cells, and cultural interstitial cells and strips of muscle. Core C will provide molecular and morphological support by preparing molecular probes and performing a range morphological analyses using light and electron microscopy. Together the Projects and Cores will provide a rigorous, highly focused investigation of the cellular mechanisms that regulate smooth muscles. The results will greatly expand our understanding of gastrointestinal motility, and provide a basis for the development of therapeutic agents for motility disorders.
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