The general objective of the work in this group is to define the role of microRNAs (miRNAs) in metabolically interesting tissues, such as β-cells, fat, liver and muscle, and in diabetes development. We believe that the understanding of the fine-tuning interplay between miRNAs and their target genes will give us a new view of the physiology and pathophysiology of these tissues.
The specific goals are to;
1) Asses the expression profile and the signature of miRNAs in human and mouse islets as well as in isolated beta-cells during physiological and inflammatory stimuli,
2) Define the biological consequences of miRNAs deficiency during beta-cell development, function and in response to inflammatory stimuli
3) Asses the expression profile of miRNAs in muscle and adipose tissue during different conditions
4) Evaluate the possibility of polymorphisms in genes coding for miRNAs or their target proteins that could increase the risk of diabetes development.
MicroRNAs are 21-23 nucleotide non-coding RNAs processed from doublestranded hairpin precursors.
Mature microRNAs function as negative regulators of specific target mRNA.
MicroRNAs regulates gene-expression by interacting with their target(s) through imprecise basepairing, resulting in arrest of translation.
The biogenesis of miRNA
Pri-miRNA is formed through synthesis of RNA from DNA (transcription) and is cleaved by the nuclear RNas III enzym Drosha to from pre-miRNA which has a hairpin structure with an imperfect stem-loop. Pre-miRNA consists of ~70 nt, 1-4 nt 3’ overhang, 25-30 nt base-pairing segments and relatively short loops.
Pre-miRNA is transported out of the nucleus and into the cytosol by a GTP-dependent transport protein called Exportin 5.The mature miRNA is formed as a 21-23 nt miRNA:miRNA duplex with the help of Dicer. Dicer belongs to the RNas III family and consist of several domains. Dicer cleaves double stranded DNA and hairpin RNA into small RNA; siRNA and miRNA, respectively. The miRNA:miRNA duplex complex is disrupted and one strand is incorporated into the RISC*-complex.
The RISC complex (RISC= RNA induced silencing complex) is an endonucleas.
RISC can be divided into two types
1) Cleaving (preferably siRNA/RISC)
2) None-cleaving (miRNA/RISC).
One of the factors that decide whether it will be a cleaving or none-cleaving RISC-complex is the type of AGO-protein (AGO= Argonaute; A family of key components in the RISC complex).
1. Micro-RNA expression differences in glucose-sensitive tissues under normal and pathophysiological conditions (Corrado Cilio, Lena Eliasson, Jonathan Esguerra, Caroline Bolmesson, Dina Speidel)
2. Beta cell specific miRNA deficiency induce defective insulin secretion and diabetes mellitus (Corrado Cilio, Lena Eliasson, Caroline Bolmesson, Martins Kalis, Jonathan Esguerra, Dina Speidel and Anna Wendt)
Last updated: October 22, 2010
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