ARHGAP21 is a RhoGAP that participates processes like insulin secretion in beta cell lineage, cell proliferation in prostate tumor cells and interaction with small G proteins, and cytoskeletal organization in different cell types. The gene and the insulin content in addition to a number of proteins related to secretion of the hormone, are significantly increased after birth, resulting in increased insulin secretion by various stimuli in the beta cell. Especially Pdx-1 transcription factor stands as a maturation protein secretory response. Reducing the ARHGAP21 content in the animal model ARHGAP21-Heterozygote (ARHGAP21-Het) resulted in impairment in insulin secretion stimulated by glucose, reduced insulin content, as well as reduced gene expression of Pdx-1 in adult mice islets. Thus, it is possible that ARHGAP21 participates in key cellular mechanisms for insulin synthesis and proper functioning of pancreatic islet also throughout the animal's life. Due to decreased gene expression of Pdx-1 and insulin content, our hypothesis is that ARHGAP21 participates in cellular mechanisms related to the development of pancreatic islet. The aim of this project is to evaluate the formation of the islet at different stages of development: in utero, post-natal, young and adult. It will be performed histological analysis of the endocrine pancreas, gene expression of proteins that are important for the development of islet and insulin secretion (Ngn-3, Pdx-1, MafA, Cx36, Glut-2 and insulin), in full pancreas or in isolated islets. Immunofluorescence of insulin, glucagon and somatostatin will be evaluated to monitor the progress of pancreatic islet architecture throughout the life of ARHGAP21-Het mice. This project will improve our understanding of the processes that coordinate the formation of pancreatic islet and insulin synthesis in the beta cell, providing thus subsidies to enable therapies that enhance insulin production and maturation of secretory response to glucose in the pancreatic islet.
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