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Overview | Research directions | Group members | Collaborations | Selected Publications | Funding

Overview

RNA impacts nearly every aspect of gene expression and it is now clear that the majority of human genetic diseases are caused by mistakes in RNA metabolism. It has become progressively evident that RNA is not just a carrier of genetic information, but also a catalyst and a guide for sequence-specific recognition and processing of other RNA molecules. Progress in our understanding of RNA biology has made it possible to identify RNA molecules as targets of therapeutic intervention and to use RNA as a tool for functional studies and as a novel therapeutic molecule to treat human disease. Since a few years, RNA-based techniques (RNA interference, antisense RNA etc.) are becoming more and more useful in gene therapy and applied research.

A description of the laboratory ongoing research, its significance and potential applications can be found here.
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Research directions

  • microRNAs (miRNAs). These are ca. 21 nt regulatory RNAs that control development and differentiation acting as post-transcriptional negative regulators of the expression of key target genes. Recent studies have demonstrated that there is altered expression of miRNA genes in several human malignancies and that miRNAs may act as oncogenes or tumour suppressors. MiRNAs are now also exploited as diagnostic and prognostic biomarkers. We carry out a functional analysis of the miRNAs specifically over- or under-expressed in lung cancers, melanoma, epithelial ovarian cancers and neurodegenerative diseases (e.g. Frontotemporal dementia) search for their target genes and investigate their role in pathogenesis;
  • Antisense RNA-induced exon skipping in gene therapy. The importance of alternative splicingfor the diversity of the proteome and the large number of genetic diseases that are due to splicing defects call for methods to modulate alternative splicing decisions. Although splicing can be modulated by antisense oligonucleotides, this approach is confronted with problems of efficient delivery and the need for repeated administrations of large amounts of oligonucleotides. Therefore, we developed a method to induce the efficient and specific skipping of an exon with the help of the U1 small nuclear RNA involved in pre-messenger RNA splicing in the nucleus. Antisense U1 snRNA-induced exon skipping has been successfully employed to devise a therapeutic strategy for Duchenne Muscular Dystrophy. We are now exploring the possibility to apply antisense U1 snRNA-induced exon skipping to other genetic disorders, such as Frontotemporal dementia, retinal dystrophies and metabolic diseases.

Group members

  • Michela A. Denti, PI
  • Simone Detassis, PhD Student
  • Bruno Evaristo De Almeida Fantinatti, PostDoc (visiting from Universidade Estadual Paulista, Botucatu, Brasil)

Collaborations

  • Nikolaos Balatsos, Dept. of Biochemistry and Biotechnology, University of Thessaly, Greece
  • Mattia Barbareschi, Unit of Surgical Pathology, S.Chiara Hospital, Trento, Italy
  • Jürgen Borlak, Hannover Medical School, Germany
  •           Annamaria Confaloni, Istituto Superiore di Sanità, Roma, Italy
  •           Flavia Ravelli, Dept. of Physics, University of Trento
  • Rohan de Silva, Reta Lila Weston Institute, University College London, UK
  • Catherine Greene, Royal College of Surgeons in Ireland, Dublin, Ireland
  • Amelia Morrone, Sezione Malattie Metaboliche e Muscolari Ereditarie, Azienda Ospedaliero Universitaria Meyer, Firenze, Italy
  • Marco Venturin, Dept. of Medical Biotechnology and Translational Medicine, University of Milano, Italy

Selected publications

Detassis S, Grasso M, Del Vescovo V, Denti MA “microRNAs Make the Call in Cancer Personalized Medicine” Front. Cell Dev. Biol. 5:86 doi: 10.3389/fcell.2017.00086

 

Godfrey C, Desviat LR, Smedsrod B, Piétri-Rouxel F, Denti MA, Disterer P, Lorain S, Nogales-Gadea G, Sardone V, Anwar R, El Andaloussi S, Lehto T, Khoo B, Brolin Hjortkjaer C, van Roon-Mom WMC, Goyenvalle A, Aartsma-Rus A, Arechavala-Gomeza V “Delivery is key: lessons learnt from developing splice switching antisense therapy” 2017 EMBO Molecular Medicine doi:10.15252/emmm.201607199

 

Masè M, Grasso MAvogaro L, D'Amato E, Tessarolo F, Graffigna A, Denti MA*, Ravelli F*. “Selection of reference genes is critical for miRNA expression analysis in human cardiac tissue. A focus on atrial fibrillation.” 2017 Sci. Rep. 7:41127 | DOI: 10.1038/srep41127 IF= 5.228 rdcu.be/oKcn *equally contributing

 

Ferri L, Covello G, Caciotti A, Guerrini R, Denti MA*, Morrone A* "Double-target Antisense U1snRNAs Correct Mis-splicing Due to c.639+861C>T and c.639+919G>A GLA Deep Intronic Mutations" 2016 Molecular Therapy Nucleic Acids 5, e380; doi:10.1038/mtna.2016.88 http://www.nature.com/mtna/journal/v5/n10/full/mtna201688a.html *equally contributing

 

Moncini S, Lunghi M, Valmadre A, Grasso MDel Vescovo V, Riva P, Denti MA, Venturin M The miR-15/107 Family of microRNA Genes Regulates CDK5R1/p35 with Implications for Alzheimer's Disease Pathogenesis. 2016 Mol. Neurobiol., doi:10.1007/s12035-016-0002-4

 

Piscopo P, Grasso M, Fontana F, Crestini A, Puopolo M, Del Vescovo V, Venerosi A, Calamandrei G, Vencken SF, Greene CM, Confaloni A, Denti MA "Reduced miR-659-3p levels correlate with progranulin increase in hypoxic conditions: implications for frontotemporal dementia" 2016 Front Mol Neurosci doi: 10.3389/fnmol.2016.00031

 

Grasso M, Fontana F, Denti MA “Circulating cell-free microRNAs as biomarkers for neurodegenerative diseases” in “Frontiers in Neurotherapeutics: Mapping Nervous System Diseases via microRNAs” Christian Barbato and Francesca Ruberti (Eds.) CRC Press-Taylor & Francis Group (Boca Raton FL, USA). 2016

 

Del Vescovo V, Denti MA “microRNA and lung cancer” in “microRNA: Cancer. From molecular biology to clinical practice” Gaetano Santulli (Ed.) Springer 2015 Adv Exp Med Biol. 2015;889:153-177 889 ISBN 978-3-319-23729-9

 

Grasso M, Piscopo P, Crestini A, Confaloni A, Denti MA “Circulating microRNAs in neurodegenerative diseases” in “Circulating microRNAs in disease diagnostics and their potential biological relevance” Peter Igaz (Ed.) Springer 2015 EXS. 106:151-69. doi: 10.1007/978-3-0348-0955-9_7

 

Fontana F, Siva K, Denti MA “A network in Fronto Temporal Dementia - an RNA perspective” 2015 Front Mol Neurosci 8:9 doi: 10.3389/fnmol.2015.00009 

 

Ricci L, Del Vescovo V, Cantaloni C, Grasso M, Barbareschi M, Denti MA “Statistical analysis of a Bayesian classifier based on the expression of miRNAs” 2015 BMC Bioinformatics. 16(1):287. doi: 10.1186/s12859-015-0715-9 

 

Bacchi N, Messina A, Burtscher V, Dassi E, Provenzano G, Bozzi Y, Demontis GC, Koschak A*, Denti MA*, Casarosa S* “A new splicing isoform of Cacna2d4 mimicking the effects of c.2451insC mutation in the retina. Novel molecular and electrophysiological insights.” 2015 Invest Ophthalmol Vis Sci. 56:4846-56. doi: 10.1167/iovs.15-16410. *equally contributing

 

Grasso M, Piscopo P, Confaloni A, Denti MA “Circulating miRNAs as biomakers for neurodegenerative diseases” 2014 Molecules 19:6891-6910. doi:10.3390/molecules19056891 

 

Siva K, Covello G, Denti MA “Exon-skipping Antisense Oligonucleotides to Correct Missplicing in Neurogenetic Diseases” Nucl. Acids Therap. 2014 24: 69-86. doi:10.1089/nat.2013.0461 

 

Bacchi N, Casarosa S*, Denti MA* “Splicing-correcting therapeutic approaches for retinal dystrophies: where endogenous gene regulation and specificity matter.” 2014 Invest Ophthalmol Visual Sci. 55:3285-94. doi: 10.1167/iovs.14-14544. *equally contributing 

 

Dassi E, Ballarini A, Covello G, HTM CMB2013, Quattrone A, Jousson O, DeSanctis V, Bertorelli R, Denti MA, Segata N “Enhanced microbial diversity in the saliva microbiome induced by short-term probiotic intake revealed by 16S rRNA sequencing on the IonTorrent PGM platform” J. Biotechnol. 2014 doi:10.1016/j.jbiotec.2014.03.024 

 

Covello G, Siva K, Adami V, Denti MA “An electroporation protocol for efficient DNA transfection in PC12 cells.” Cytotechnology 2014 66(4):543-553 DOI: 10.1007/s10616-013-9608-9 

 

Bisio A, De Sanctis V, Del Vescovo V, Denti MA, Jegga AG, Inga A, Ciribilli Y “Identification of new p53 target microRNAs by bioinformatics and functional analysis” BMC Cancer 2013 13:552 IF=3.33 SJR=1.403 Cit=16 

 

Del Vescovo V, Grasso M, Barbareschi M, Denti MA, “microRNAs as lung cancer biomarkers" World Journal Clinical Oncology 2014 5(4):604-620; doi:10.5306/wjco.v5.i4.604 

 

Del Vescovo V, Meier T, Inga A, Denti MA*, Borlak J* “A Cross-Platform Comparison of Affymetrix and Agilent Microarrays Reveals Discordant miRNA Expression in Lung Tumors of c-Raf Transgenic Mice” PLoS ONE  2013 8(11): e78870. doi:10.1371/journal.pone.0078870 * equally contributing 

 

Denti MA, Barbareschi M, Grasso M, Cantaloni C "Small RNA molecules of great utility as diagnostic biomarkers in lung cancer" European Pharmaceutical Review 2013 18:35-37 

 

Denti MA, Viero G, Provenzani A, Quattrone A, Macchi P "mRNA fate: life and death of the mRNA in the cytoplasm" RNA Biol 2013 10:360-366. 

 

Barbareschi M, Cantaloni C, Del Vescovo V, Cavazza A, Monica V, Carella R, Rossi G, Morelli L, Cucino A, Silvestri M, Tirone G, Pelosi G, Graziano P, Papotti M, Dalla Palma P, Doglioni C, Denti MA. “Heterogeneity of large cell carcinoma of the lung: an immunophenotypic and miRNA based analysis”. Am. J. Clin. Pathol. 2011 136:773-782. IF=2,504 

 

Del Vescovo V, Cantaloni C, Cucino A, Girlando S, Silvestri M, Bragantini E, Fasanella S, Cuorvo LV, Dalla Palma P, Rossi G, Papotti M, Pelosi G, Graziano P, Cavazza A, Denti MA, Barbareschi M.  "miR-205 expression levels in non-small cell lung cancer do not always distinguish adenocarcinomas from squamous cell carcinomas." Am. J. Surg. Pathol. 2011 35:268-275. 

 

Funding

European Commission, Marie Skłodowska-Curie Actions - Reasearch and Innovation Staff Exchange“miRNA-DisEASY:microRNA biomarkers in an innovative biophotonic sensor kit for high-specific diagnosis

Italian Ministry of Health -RF-2011-02347694 “Therapeutic correction of mis-spliced RNA transcripts and of protein conformational defects in Lysosomal Storage Disorders” 

Provincia Autonoma di Trento - Grandi progetti 2012: TRANSCRAPPLE     “Transcriptional and Post-transcriptional regulation of apple fruit development