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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Academic Research Enhancement Awards (AREA) (R15)
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Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
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Karp, Robert W
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College at Brockport
Schools of Arts and Sciences
United States
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Rich, Adam (2018) Improved Imaging of Zebrafish Motility. Neurogastroenterol Motil 30:e13435
Brady, Clayton; Denora, Maxwell; Shannon, Ian et al. (2017) Intestinal Transit Time and Cortisol-Mediated Stress in Zebrafish. Zebrafish 14:404-410
Rich, Adam; Gordon, Scott; Brown, Chris et al. (2013) Kit signaling is required for development of coordinated motility patterns in zebrafish gastrointestinal tract. Zebrafish 10:154-60
Ball, Evan R; Matsuda, Miho M; Dye, Louis et al. (2012) Ultra-structural identification of interstitial cells of Cajal in the zebrafish Danio rerio. Cell Tissue Res 349:483-91