The overall hypothesis addressed in this work is that Ca-regulatory hormonal peptides, especially parathyroid hormone (PTH) and calcitonin gene-related peptide (CGRP), play important roles in regulation of gut function. PTH is a highly effective relaxant of GI smooth muscle. This project will examine in detail the nature of the GI PTH receptors and the second messengers involved. Rat GI smooth muscle and mucosa will be studied using standard ligand binding techniques, receptor chemical cross- linking, and autoradiography in order to compare GI receptors to classical PTH receptors in bone and kidney and to localize the receptors to specific GI cells. Second messengers to be examined include cyclic nucleotides, intracellular Ca++, and inositol phosphates. Also addressed in the hypothesis that PTH-related protein (PTHrP), a newly discovered tumor- derived peptide involved in humoral hypercalcemia of malignancy, is present normally in GI mucosal or muscle cells and acts locally as a paracrine or autocrine factor to regulate GI events. Molecular biological technology will be used to search for PTHrP mRNA in the gut and, by in situ hybridization histochemistry, to localize the mRNA to specific GI cells. Immunocytochemistry will be employed concurrently to localize PTHrP itself. Developmental changes in association with gestation, lactation, aging, and wound healing will be examined. The physiological significance of the effect of PTH-like peptides in the gut will be examined by studying nonabsorbable markers in vivo in the rat gut to determine the influence of these peptides on GI motility. CGRP, also known to affect GI function, especially contractility, also will be studied using the approaches outlined for PTHrP. Receptors in rat and pig GI tissue will be characterized, second messengers will be identified, and the localization of mRNA and the peptide itself will be studied using hybridization and immunocytochemical techniques. The studies will help elucidate the physiological importance of PTRrP, a new peptide functionally associated at present only with tumor tissue. The work ultimately should establish new roles for Ca-related peptides in the gut, clarify the mechanisms involved, promote our understanding of their roles in health and disease, and enable us to employ these peptides or their analogs as therapeutic agents.

Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Type
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555
Bhatia, Vandanajay; Cao, Yanna; Ko, Tien C et al. (2016) Parathyroid Hormone-Related Protein Interacts With the Transforming Growth Factor-?/Bone Morphogenetic Protein-2/Gremlin Signaling Pathway to Regulate Proinflammatory and Profibrotic Mediators in Pancreatic Acinar and Stellate Cells. Pancreas 45:659-70
Staloch, Dustin; Gao, Xuxia; Liu, Ka et al. (2015) Gremlin is a key pro-fibrogenic factor in chronic pancreatitis. J Mol Med (Berl) 93:1085-1093
Mrazek, Amy A; Porro, Laura J; Bhatia, Vandanajay et al. (2015) Apigenin inhibits pancreatic stellate cell activity in pancreatitis. J Surg Res 196:8-16
Gao, Xuxia; Cao, Yanna; Staloch, Dustin A et al. (2014) Bone morphogenetic protein signaling protects against cerulein-induced pancreatic fibrosis. PLoS One 9:e89114
Bhatia, Vandanajay; Rastellini, Cristiana; Han, Song et al. (2014) Acinar cell-specific knockout of the PTHrP gene decreases the proinflammatory and profibrotic responses in pancreatitis. Am J Physiol Gastrointest Liver Physiol 307:G533-49
Gao, Xuxia; Cao, Yanna; Yang, Wenli et al. (2013) BMP2 inhibits TGF-?-induced pancreatic stellate cell activation and extracellular matrix formation. Am J Physiol Gastrointest Liver Physiol 304:G804-13
Deng, Xiyun; Cao, Yanna; Liu, Yan et al. (2013) Overexpression of Evi-1 oncoprotein represses TGF-? signaling in colorectal cancer. Mol Carcinog 52:255-264
Cao, Yanna; Zhang, Weili; Gao, Xuxia et al. (2013) PTHrP is a novel mediator for TGF-?-induced apoptosis. Regul Pept 184:40-6
Cao, Yanna; Yang, Wenli; Tyler, Matthew A et al. (2013) Noggin attenuates cerulein-induced acute pancreatitis and impaired autophagy. Pancreas 42:301-7
Okamura, Daiki; Starr, Marlene E; Lee, Eun Y et al. (2012) Age-dependent vulnerability to experimental acute pancreatitis is associated with increased systemic inflammation and thrombosis. Aging Cell 11:760-9

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