Treatment options for GI motility disorders are limited, reflecting the need for new model systems and for identification of new, effective drug targets. The specific objective of this AREA proposal is to establish the zebrafish as a model system to study the role of ICC in GI motility. Coordinated gastrointestinal (GI) motility patterns are controlled by complex interactions between smooth muscle cells, interstitial cells of Cajal (ICC), and enteric neurons. GI dysmotility affects many patients, for example, gastroparesis occurs in ~50% of diabetic patients and is associated with ICC deficits. ICC are necessary for the spontaneous and rhythmic patterns of coordinated muscular contractions that mix and propel luminal contents. Expression of the Kit receptor tyrosine kinase is used to identify ICC. Kit signaling is necessary for ICC development and maintenance, and is stimulated by Kit ligand (KL, also called stem cell factor). Two forms of KL, one soluble and one membrane bound, are expressed in the GI tract. This AREA proposal builds on previous work showing the presence of ICC in the zebrafish GI tract and will determine the spatiotemporal expression patterns for kitla and kitlb, orthologues for soluble and membrane bound KL, using in-situ hybridization and real time PCR. The working hypothesis of this proposal is that kitla supports development of ICC progenitors, and kitlb supports ICC maturation. This work will contribute to the understanding of mechanisms by which ICC develop and are maintained in human health and disease, and will continue to establish the zebrafish as a model system to study the role of ICC in GI motility.
New model systems are needed to help identify novel drug targets for the effective treatment of gastrointestinal motility disorders such as constipation, gastroparesis, and bloating. This AREA proposal will establish the zebrafish as a model system to study the role of ICC in GI motility, and will contribute to a better understanding of the mechanisms that support ICC development in human health and disease.
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