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Studying micro RNAs as biomarkers for diagnosis and novel therapeutic targets in muscular disorders
Supervisors: Professor Francesco Muntoni and Dr Jennifer Morgan
In this project we will conduct a comprehensive miRNA profiling in muscle tissue and biological fluids, such as serum or urine, from different types of muscular dystrophies (MD) in order to gain detailed understanding of the miRNA pathways involved in pathogenic process and the utilization of the dysregulated miRNAs as non-invasive biomarkers.
Micro RNAs are small RNA sequences (~22 nucleotides) that act as post-transcriptional regulators through imperfect base pairing between the miRNA and the target mRNA leading to repression of the target gene by inducing mRNA degradation or translational inhibition. A single RNA can regulate the expression of hundreds of mRNAs due to the imperfect pairing and over 60% of all genes are targeted by miRNAs. Micro RNAs are also found to be conserved in different organisms suggesting the vital role of these small RNA molecules in regulation of wide range of biological processes such as development, differentiation, proliferation and cell death. Several studies shed light into the role of microRNAs in the pathological pathways activated in normal and diseased skeletal muscle. MicroRNA sequencing (miRNA-seq) is a novel tool that allows the discovery of previously uncharacterized miRNAs, examining of tissue specific expression patterns and identifying different isoforms of miRNAs. In order to identify distinctive miRNAs pathways we will perform miRNA sequencing in muscle biopsies from patients and disease controls. We will also carry out miRNA sequencing in serum samples with the aim to identify non-invasive biomarkers..
During the first year the student will have an introduction programme consisting of dedicated neuromuscular lecture programme, tutorials and clinic visits to cover relevant aspects of neuromuscular diseases and will be trained for the preparation of the samples.
Year 2. She will be trained in-house in the bioinformatic techniques required during the project. Confirmation of the results by real-time PCR and analysis of additional cases.
Year 3. Analysis of the results and their confermation by real-time PCR.
The project aims to further understand the additional element of regulation of muscle function mediated by miRNAs in different types of muscular dystrophies and to discover miRNAs that can be utilised as non-invasive biomarkers for monitoring disease progression.
The study will be part of “Neuromics”, a recently funded project by European Commission 7th Framework Programme on Research, Technological Development and Demonstration
1) Eisenberg I, Eran A, Nishino I, Moggio M, Lamperti C, Amato AA, Lidov HG, Kang PB, North KN, Mitrani-Rosenbaum S, Flanigan KM, Neely LA, Whitney D, Beggs AH, Kohane IS, Kunkel LM: Distinctive patterns of microRNA expression in primary muscular disorders. Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17016-21.
2) Greco S, De Simone M, Colussi C, Zaccagnini G, Fasanaro P, Pescatori M, Cardani R, Perbellini R, Isaia E, Sale P, Meola G, Capogrossi MC, Gaetano C, Martelli F. Common micro-RNA signature in skeletal muscle damage and regeneration induced by Duchenne muscular dystrophy and acute ischemia. FASEB J. 2009 Oct;23(10):3335-46.
3) Cacchiarelli D, Incitti T, Martone J, Cesana M, Cazzella V, Santini T, Sthandier O, Bozzoni I. miR-31 modulates dystrophin expression: new implications for Duchenne muscular dystrophy therapy. EMBO Rep. 2011 Feb;12(2):136-41.
4) Cacchiarelli D, Legnini I, Martone J, Cazzella V, D'Amico A, Bertini E, Bozzoni I. miRNAs as serum biomarkers for Duchenne muscular dystrophy. EMBO Mol Med. 2011 May;3(5):258-65. doi: 10.1002/emmm.201100133.