BMPs (Bone Morphogenetic Protein) and their receptors are expressed in different cell types during all steps of body growth and development. BMPs have broad biological actions, which depend on the recruitment of the intracellular signaling proteins SMADs, co-factors and the cross talk with other signaling pathways. SMADs 1/5/8 are specific receptor-regulated SMADs (BR-SMADs). It has already been described the expression of SMADs in both human and rodent pancreatic islets; it has also been demonstrated the participation of the BMP receptor BMPR1A in the glucose-stimulated insulin secretion (GSIS). Among the BMPs, BMP-9 has been suggested as putative therapeutical target for Type 2 diabetes mellitus. Our group has demonstrated that (i) the expression and maturation of hepatic BMP-9 are reduced in animal models of insulin resistance; (ii) BMP-9 expression depends on hepatic insulin action; and (iii) BMP-9 signaling in skeletal muscle is attenuated in the insulin resistant state. Unpublished results showed that the RNAi-based BR-SMADs knockdown in INS-1 cells changed the expression pattern of genes related to insulin exocytosis, particularly several members of SNARE proteins. Although several evidences point to the relevance of BMP-SMADs signaling on beta cell function, the molecular mechanism is not settled yet. The aim of this project is to dissect the molecular events regulated by BMP-9, focusing on the regulation of SNAREs proteins and the GSIS. For this we will perform different methodologies (RIA, immunohistochemistry, RNAi transfection, ChIP assay, qPCR and western blot) using INS-1 and primary beta cells and isolated neonatal pancreatic islets.
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