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Role of KSRP in post-transcriptional regulation and beta cell function in INS-1E lineage and pancreatic islet


Dysfunctions in pancreatic beta cells can lead to impaired insulin production and secretion, cell death, and type 2 Diabetes mellitus (DM2). Understanding the mechanisms that regulate the synthesis of proteins involved in beta cell function and survival is of fundamental importance to understand how such dysfunctions could be avoided. The KH-type splicing regulatory protein (KSRP) modulates cellular gene expression through post-transcriptional regulation, participating in mechanisms such as alternative splicing, mRNA degradation and primary processing and maturation of microRNAs. Phosphorylation by AKT can prevent KSRP from binding to specific mRNAs or recruiting the mRNA degradation machinery and, at the same time, it can enhance KSRP's interaction with microRNA maturation complexes. KSRP expression has been reported in pancreatic beta cells, and we believe that it regulates the expression of key components involved in such processes. Our group initiated a study of the role of KSRP in the INS-1E mouse beta cell line. For this, we developed KSRP knock-down and overexpression models in INS-1E beta cells, and we observed that in such models there are alterations in insulin content, response to endoplasmic reticulum stress and cell survival. Continuing the study, in this project we aim to evaluate the role of KSRP in post-transcriptional regulation in pancreatic beta cells, through the analysis of microRNAs, essential to the insular function. For this, we will use a more efficient KSRP expression inhibition system through lentiviral infection, in both beta cell lineage and isolated mouse islets. Thus, this project may contribute to the elucidation of relevant mechanisms to the synthesis and regulation of beta cell proteins and, therefore, to the development of more effective therapeutic strategies against DM2. (AU)

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