Forces developed within the intestine are regulated by multiple factors: wall thickness, wall composition, lumen radius, and the timing and degree of activation of the muscle cells. Thus, both non-contractile activities (e.g. smooth muscle cell proliferation and protein synthesis) and contractile activities are determinants of motility functions. Contractile activities of the intestine have been described during a number of normal and pathological conditions (e.g. intestinal bypass, intestinal resection, Crohn's disease, bacterial infection, mechanical obstruction, pseudoobstruction, and aging); however, little is known about non-contractile activities. In many of these conditions there is remodeling of the muscle layers expressed as a thickening and/or a change in diameter. Although remodeling occurs, neither the muscular alterations nor the mechanisms responsible for the remodeling have been studied in detail. These gaps in our knowledge will be addressed by using one of the above-mentioned conditions as a model. The overall goals of the research outlined in this proposal are to determine: 1) the structural, molecular, biochemical, and functional alterations that occur in intestinal muscle, and 2) the initiating factors and mediators inducing the alterations during remodeling. Rats will undergo bypass of 70% of their mid small intestine. Smooth muscle from the circular and longitudinal layers will be evaluated for changes in cell size and number, contractile protein content and isoform distribution, total RNA, the concentrations of mRNA's that code for contractile and non-contractile proteins, myosin light chain kinase activity, and contractility. Initiating factors and mediators of the remodeling will be investigated by varying the contents of the intestine, and the hormonal and/or neural state of the animal The involvement of insulin-like growth factor I , interleukin 1beta, platelet derived growth factor and ornithine decarboxylase will be investigated by monitoring their activities, protein levels, and/or mRNA levels; and, where possible, by administering agonists and antagonists of these mediators. Finally the time course of the remodeling will be correlated with the time course of changes in intestinal transit and with patterns of weight gain to determine interrelationships among contractile and non-contractile functions of the muscle, and the role of these interrelationships in the ability of the intestine to adapt.
