DEVELOPMENTAL ASPECTS OF UPPER GASTROINTESTINAL MOTILITY

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Gastric motor dysfunction results in significant morbidity which is particularly striking during the newborn period. During growth and development the stomach is required to deal with changing dietary intake. The changes in dietary constituents during growth and development from predominantly liquid to mixed solid liquid meals places an increasing burden on the antrum which is required to triturate solids. The newborn antrum generates less force than adult antrum and our preliminary data indicate that newborn antral smooth muscle cells undergo biochemical changes that correlate with these changes in dietary intake. The specific aims of this proposal are to determine what developmental changes occur in the stomach, by examining specifically: 1) the source of calcium utilized for agonist induced contraction 2) the intracellular pathways which are followed during contraction 3) the contractile proteins responsible for generation of force. We will monitor changes in these parameters over the first 6 weeks of life in the kitten and compare them to the adult. We propose to study the maturation of the contractile response to cholinergic stimulation in the antrum which in the newborn is totally dependent on utilization of Ca from extracellular sources and proceeds via a calmodulin independent pathway to the adult antrum which is able to utilize Ca from both intracellular and extracellular sources and proceeds via a calmodulin dependent pathway. Concurrently we will study the quantitative and qualitative biochemical changes in the contractile proteins responsible for the generation of force. This developmental process is important for the transformation of the antrum into a region which is able to generate greater force and triturate solids. In summary we will focus on the hypothesis that during the growth process contractile agonists (acetylcholine and CCK-OP) may preferentially utilize different sources of Ca and activate different intracellular pathways. We can follow this maturational process during the period of infancy, at a time when the ability to handle changes in diet is crucial for optimal growth. We believe that this type of expertise and focus is critical to understanding the development of gastric motility during this transitional period. The studies outlined will shed new light on the maturation of the regulatory mechanisms responsible for gastric contraction.