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School of Medicine

Dr Mark Lindsay PhD

Honorary Reader in Biopharmaceutics

Room 3.106

Stopford Building

Oxford Road

Manchester M13 9PT

 

Research

Role of microRNAs and long non-coding RNAs in inflammatory and respiratory disease

 

Approximately 2% of the bases in the human genome code for protein. However, a variety of experimental approaches suggest that the over-whelming majority of the human genome is transcribed into non-(protein)-coding RNA. These RNAs can be broadly divided into three groups: house-keeping, short and long non-coding RNA (1;2).

House-keeping non-coding RNAs: House-keeping non-coding RNAs typically have short sequences, conserved secondary structures and may be transcribed by RNA polymerase I, II or III. These include well characterised families such as the transfer RNAs and ribosomal RNAs.

Small non-coding RNAs: The advent of deep-sequencing has resulted in the identification of at least 12 families of small non-coding RNAs (sncRNA) in mammalian cells. The three best characterised are the piwi-associated RNAs (piRNAs), endogenous small interfering RNAs (siRNAs) and microRNAs (miRNAs), which all employ argonaute (Ago) proteins to guide sequence-specific regulation of transcription and/or translation.

Long non-coding RNA: The majority (> 80%) of non-protein coding RNA is defined as long non-coding RNAs (> 200 nucleotides), and this class is the least well-understood. Since much of this lncRNA appeared to be non-conserved, it was initially believed that these represented transcriptional ‘noise’ following activation of RNA polymerase II. However, recent reports have demonstrated that lncRNA contain conserved secondary structure/splicing patterns, that their expression is cell- and developmentally-specific and is mediated through activation of common transcription factors including p53, NF-kB, Sox2, Oct4 and Nanog (1;2). Arguably the most interestingly function of lncRNAs is the epigenetic regulation of transcription. Two recent papers that examined the chromatin signature that defines actively transcribing genes have identified over 3000 novel long non-coding RNAs that are associated with intergenic regions (4;5). Functional analysis of these lncRNAs has shown that ~ 20-40% are associated with the polycomb repressive complex 2 (PRC2), a methyltransferase that trimethylates histone H3 at lysine 27 (K27) to repress transcription. Using siRNAs to down-regulate individual lncRNAs, the authors demonstrated that this reversed PRC2 repression and resulted in increased expression of distinct group of genes that are known to be attenuated by PRC2. Given these observations, we speculate that individual lncRNAs can act like transcription factors and miRNAs to regulate the expression of multiple proteins.
 

 

At the present time, members of group are involviong in investigating:

1.  The role of miR-146a in the innate and adaptive immune response

2.  The role of miRNAs and long non-coding RNAs in asthma and chronic obstructive pulmonary disease

3.  The role of long non-coding RNAs in the innate and adaptive immune response

4.  The utility of oligonucleotide-based approaches as a novel therapeutic approach to treatment of inflammatory and respiratory disease

 

Publications

2009

  • Perry, M., Williams, A., Tsitsiou, E., Larner-Svensson, H. & Lindsay, M (2009). Divergent intracellular pathways regulate interleukin-1beta-induced miR-146a and miR-146b expression and chemokine release in human alveolar epithelial cells. FEBS Lett, 583(20), 3349-55. eScholarID:79343 | PMID:19786024 | DOI:10.1016/j.febslet.2009.09.038
  • Tsitsiou E, Lindsay MMA. (2009). microRNAs and the immune response. Curr Opin Pharmacol, eScholarID:1d19833 | DOI:10.1016/j.coph.2009.05.003
  • Williams A, Larner-Svensson H, Perry M, Campbell G, Herrick SE, Adcock I, Erjefalt J, Chung K, Lindsay MMA. (2009). MicroRNA expression profiling in mild asthmatic human airways and effect of corticosteroid therapy. PLoS One, 4( 6), eScholarID:1d19825 | DOI:10.1371/journal.pone.0005889

2008

  • Lindsay MMA. (2008). microRNAs and the immune response. Trends Immunol, 29( 7), 343-51. eScholarID:1d19836 | DOI:10.1016/j.it.2008.04.004
  • Moschos S, Spinks K, Williams A, Lindsay MMA. (2008). Targeting the lung using siRNA and antisense based oligonucleotides. Curr Pharm Des, 14( 34), 3620-7. eScholarID:1d19834
  • Perry M, Moschos S, Williams A, Shepherd N, Larner-Svensson H, Lindsay MMA. (2008). Rapid changes in microRNA-146a expression negatively regulate the IL-1beta-induced inflammatory response in human lung alveolar epithelial cells. J Immunol, 180( 8), 5689-98. eScholarID:1d19837
  • Williams A, Perry M, Moschos S, Larner-Svensson H, Lindsay MMA. (2008). Role of miRNA-146a in the regulation of the innate immune response and cancer. Biochem Soc Trans, 36( Pt 6), 1211-5. eScholarID:1d19835 | DOI:10.1042/BST0361211

2007

  • Moschos S, Williams A, Lindsay MMA. (2007). Cell-penetrating-peptide-mediated siRNA lung delivery. Biochem Soc Trans, 35( Pt 4), 807-10. eScholarID:1d19840 | DOI:10.1042/BST0350807
  • Moschos S, Williams A, Perry M, Birrell M, Belvisi M, Lindsay MMA. (2007). Expression profiling in vivo demonstrates rapid changes in lung microRNA levels following lipopolysaccharide-induced inflammation but not in the anti-inflammatory action of glucocorticoids. BMC Genomics, 8, eScholarID:1d19839 | DOI:10.1186/1471-2164-8-240
  • Moschos, S, Jones, S, Perry, M, Williams, A, Erjefalt, J, Turner, J, Barnes, P, Sproat, B, Gait, M, Lindsay, MMA. (2007). Lung delivery studies using siRNA conjugated to TAT(48-60) and penetratin reveal peptide induced reduction in gene expression and induction of innate immunity. Bioconjug Chem, 18( 5), 1450-9. eScholarID:1d19838 | DOI:10.1021/bc070077d
  • Turner J, Jones S, Moschos S, Lindsay MMA, Gait M. (2007). MALDI-TOF mass spectral analysis of siRNA degradation in serum confirms an RNAse A-like activity. Mol Biosyst, 3( 1), 43-50. eScholarID:1d19842 | DOI:10.1039/b611612d
  • Williams A, Moschos S, Perry M, Barnes P, Lindsay MMA. (2007). Maternally imprinted microRNAs are differentially expressed during mouse and human lung development. Dev Dyn, 236( 2), 572-80. eScholarID:1d19843 | DOI:10.1002/dvdy.21047
  • Williams A, Perry M, Moschos S, Lindsay MMA. (2007). microRNA expression in the aging mouse lung. BMC Genomics, 8, eScholarID:1d19841 | DOI:10.1186/1471-2164-8-172

2005

  • de Souza P, Lindsay MMA. (2005). Apoptosis as a therapeutic target for the treatment of lung disease. Curr Opin Pharmacol, 5( 3), 232-7. eScholarID:1d19846 | DOI:10.1016/j.coph.2005.01.012
  • Jones S, Christison R, Bundell K, Voyce C, Brockbank S, Newham P, Lindsay MMA. (2005). Characterisation of cell-penetrating peptide-mediated peptide delivery. Br J Pharmacol, 145( 8), 1093-102. eScholarID:1d19844 | DOI:10.1038/sj.bjp.0706279
  • Lindsay MMA. (2005). Finding new drug targets in the 21st century. Drug Discov Today, 10( 23-24), 1683-7. eScholarID:1d19845 | DOI:10.1016/S1359-6446(05)03670-6

2004

  • de Souza P, Lindsay MMA. (2004). Mammalian Sterile20-like kinase 1 and the regulation of apoptosis. Biochem Soc Trans, 32( Pt3), 485-8. eScholarID:1d19849 | DOI:10.1042/BST0320485
  • Jones S, Lindsay MMA. (2004). Overview of target validation and the impact of oligonucleotides. Curr Opin Mol Ther, 6( 5), 546-50. eScholarID:1d19847
  • Jones S, Souza P, Lindsay MMA. (2004). siRNA for gene silencing: a route to drug target discovery. Curr Opin Pharmacol, 4( 5), 522-7. eScholarID:1d19848 | DOI:10.1016/j.coph.2004.06.003

2003

  • Green I, Christison R, Voyce C, Bundell K, Lindsay MMA. (2003). Protein transduction domains: are they delivering? Trends Pharmacol Sci, 24( 5), 213-5. eScholarID:1d19853
  • Lindsay MMA. (2003). Target discovery. Nat Rev Drug Discov, 2( 10), 831-8. eScholarID:1d19851 | DOI:10.1038/nrd1202
  • Zhang X, Msc, Moilanen E, Lahti A, Hämäläinen M, Giembycz M, Barnes P, Lindsay MMA, Kankaanranta H. (2003). Regulation of eosinophil apoptosis by nitric oxide: Role of c-Jun-N-terminal kinase and signal transducer and activator of transcription 5. J Allergy Clin Immunol, 112( 1), 93-101. eScholarID:1d19852

2002

  • De Souza P, Kankaanranta H, Michael A, Barnes P, Giembycz M, Lindsay MMA. (2002). Caspase-catalyzed cleavage and activation of Mst1 correlates with eosinophil but not neutrophil apoptosis. Blood, 99( 9), 3432-8. eScholarID:1d19861
  • Kankaanranta H, Giembycz M, Barnes P, Haddad E, Saarelainen S, Zhang X, Moilanen E, Lindsay MMA. (2002). Hydrogen peroxide reverses IL-5 afforded eosinophil survival and promotes constitutive human eosinophil apoptosis. Int Arch Allergy Immunol, 127( 1), 73-8. eScholarID:1d19862
  • Lindsay MMA. (2002). Peptide-mediated cell delivery: application in protein target validation. Curr Opin Pharmacol, 2( 5), 587-94. eScholarID:1d19856
  • Zhang X, Moilanen E, Adcock I, Lindsay MMA, Kankaanranta H. (2002). Divergent effect of mometasone on human eosinophil and neutrophil apoptosis. Life Sci, 71( 13), 1523-34. eScholarID:1d19859

2001

  • Lynch O, Giembycz M, Barnes P, Lindsay MMA. (2001). Pharmacological comparison of LTB(4)-induced NADPH oxidase activation in adherent and non-adherent guinea-pig eosinophils. Br J Pharmacol, 134( 4), 797-806. eScholarID:1d19863 | DOI:10.1038/sj.bjp.0704314

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