Research

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Michael Costigan, PhD

Michael Costigan
Program:
Neurobiology Program
Department:
Department of Anesthesiology, Perioperative and Pain Medicine Research
Division
Critical Care Medicine Research
Hospital Title:
Research Associate
Academic Title:
Assistant Professor, Harvard Medical School
Research Focus Area:
Pain and regeneration
Contact Via Email
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Research Overview

I am principally interested in the reaction of the peripheral nervous system, and second order neurons of the spinal dorsal horn to axonal damage, whether these changes result in maladaptive phenotypes (chronic pain) (Costigan et al., 2009a)or adaptive ones (regeneration) (Richardson et al., 2009). My focus is developing and using truly unbiased genetic research tools to obtain an unprecedented view of these mechanisms. 

From these data we wish to glean key genes and functional cascades, in order that these mechanisms can be proven in the laboratory, always with a view to translate such knowledge into future therapies. To do this I use whole genome expression microarrays in rodents with Dr Griffin (MGH), Dr’s Moss & Fitzgerald (London, UK), and Dr’s Coppola & Geschwind (UCLA). I use genome wide SNP arrays in humans, in collaboration with Dr’s Belfer & Lariviere (Pittsburgh), as well as Dr Diatchenko (UNC). I work with Dr’s Neely & Penninger (Vienna, Austria) to search drosophila genetics for relevant phenotypes (Neely et al., 2010). 

All of these data are combined to produce strong leads which are analyzed by multiple molecular methods prior to target development in humans. Examples of such work include, 1.The identification and subsequent characterization of GTP Cyclohydrolase 1 (GCH1) as a determinant of pain sensitivity in rodents (Tegeder et al., 2006). 

Current work develops cutting edge transgenic animals to further investigate the tetrahydrobiopterin pathway in sensory neurons as well as defining other human pain targets (Costigan et al., 2010). 2.The identification and characterization of the role of the innate (Griffin et al., 2007)and the adaptive immune system (Costigan et al., 2009b)in neuropathic pain. Current work develops an understanding of how T-lymphocytes and myeloid cells interact to create neuropathic pain. 3. I am actively exploring the mechanisms of regeneration within peripheral nervous system (Mills et al., 2007) and am currently working up multiple exciting new genetic leads in this area.

Publications

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  1. Chandran V, Coppola G, Nawabi H, Omura T, Versano R, Huebner EA, Zhang A, Costigan M, Yekkirala A, Barrett L, Blesch A, Michaelevski I, Davis-Turak J, Gao F, Langfelder P, Horvath S, He Z, Benowitz L, Fainzilber M, Tuszynski M, Woolf CJ, Geschwind DH. A Systems-Level Analysis of the Peripheral Nerve Intrinsic Axonal Growth Program. Neuron. 2016 Mar 2; 89(5):956-70.
  2. Dulin JN, Antunes-Martins A, Chandran V, Costigan M, Lerch JK, Willis DE, Tuszynski MH. Transcriptomic Approaches to Neural Repair. J Neurosci. 2015 Oct 14; 35(41):13860-7.
  3. Omura T, Omura K, Tedeschi A, Riva P, Painter MW, Rojas L, Martin J, Lisi V, Huebner EA, Latremoliere A, Yin Y, Barrett LB, Singh B, Lee S, Crisman T, Gao F, Li S, Kapur K, Geschwind DH, Kosik KS, Coppola G, He Z, Carmichael ST, Benowitz LI, Costigan M, Woolf CJ. Robust Axonal Regeneration Occurs in the Injured CAST/Ei Mouse CNS. Neuron. 2015 Jun 3; 86(5):1215-27.
  4. Vicuña L, Strochlic DE, Latremoliere A, Bali KK, Simonetti M, Husainie D, Prokosch S, Riva P, Griffin RS, Njoo C, Gehrig S, Mall MA, Arnold B, Devor M, Woolf CJ, Liberles SD, Costigan M, Kuner R. The serine protease inhibitor SerpinA3N attenuates neuropathic pain by inhibiting T cell-derived leukocyte elastase. Nat Med. 2015 May; 21(5):518-23.
  5. Yang F, Fu H, Lu YF, Wang XL, Yang Y, Yang F, Yu YQ, Sun W, Wang JS, Costigan M, Chen J. Post-stroke pain hypersensitivity induced by experimental thalamic hemorrhage in rats is region-specific and demonstrates limited efficacy of gabapentin. Neurosci Bull. 2014 Dec; 30(6):887-902.
  6. Young EE, Costigan M, Herbert TA, Lariviere WR. Heritability of nociception IV: neuropathic pain assays are genetically distinct across methods of peripheral nerve injury. Pain. 2014 May; 155(5):868-80.
  7. Xie F, Fu H, Hou JF, Jiao K, Costigan M, Chen J. High energy diets-induced metabolic and prediabetic painful polyneuropathy in rats. PLoS One. 2013; 8(2):e57427.
  8. Simonetti M, Hagenston AM, Vardeh D, Freitag HE, Mauceri D, Lu J, Satagopam VP, Schneider R, Costigan M, Bading H, Kuner R. Nuclear calcium signaling in spinal neurons drives a genomic program required for persistent inflammatory pain. Neuron. 2013 Jan 9; 77(1):43-57.
  9. Neely GG, Rao S, Costigan M, Mair N, Racz I, Milinkeviciute G, Meixner A, Nayanala S, Griffin RS, Belfer I, Dai F, Smith S, Diatchenko L, Marengo S, Haubner BJ, Novatchkova M, Gibson D, Maixner W, Pospisilik JA, Hirsch E, Whishaw IQ, Zimmer A, Gupta V, Sasaki J, Kanaho Y, Sasaki T, Kress M, Woolf CJ, Penninger JM. Construction of a global pain systems network highlights phospholipid signaling as a regulator of heat nociception. PLoS Genet. 2012; 8(12):e1003071.
  10. Costigan M. Pain's peptide signature. Pain. 2012 Mar; 153(3):509-10.
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  12. Costigan M, Latremoliere A, Woolf CJ. Analgesia by inhibiting tetrahydrobiopterin synthesis. Curr Opin Pharmacol. 2012 Feb; 12(1):92-9.
  13. Ma CH, Omura T, Cobos EJ, Latrémolière A, Ghasemlou N, Brenner GJ, van Veen E, Barrett L, Sawada T, Gao F, Coppola G, Gertler F, Costigan M, Geschwind D, Woolf CJ. Accelerating axonal growth promotes motor recovery after peripheral nerve injury in mice. J Clin Invest. 2011 Nov; 121(11):4332-47.
  14. Latremoliere A, Costigan M. GCH1, BH4 and pain. Curr Pharm Biotechnol. 2011 Oct; 12(10):1728-41.
  15. Neely GG, Keene AC, Duchek P, Chang EC, Wang QP, Aksoy YA, Rosenzweig M, Costigan M, Woolf CJ, Garrity PA, Penninger JM. TrpA1 regulates thermal nociception in Drosophila. PLoS One. 2011; 6(8):e24343.
  16. Costigan M, Belfer I, Griffin RS, Dai F, Barrett LB, Coppola G, Wu T, Kiselycznyk C, Poddar M, Lu Y, Diatchenko L, Smith S, Cobos EJ, Zaykin D, Allchorne A, Gershon E, Livneh J, Shen PH, Nikolajsen L, Karppinen J, Männikkö M, Kelempisioti A, Goldman D, Maixner W, Geschwind DH, Max MB, Seltzer Z, Woolf CJ. Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1. Brain. 2010 Sep; 133(9):2519-27.
  17. Bishay P, Schmidt H, Marian C, Häussler A, Wijnvoord N, Ziebell S, Metzner J, Koch M, Myrczek T, Bechmann I, Kuner R, Costigan M, Dehghani F, Geisslinger G, Tegeder I. R-flurbiprofen reduces neuropathic pain in rodents by restoring endogenous cannabinoids. PLoS One. 2010; 5(5):e10628.
  18. Vardeh D, Wang D, Costigan M, Lazarus M, Saper CB, Woolf CJ, Fitzgerald GA, Samad TA. COX2 in CNS neural cells mediates mechanical inflammatory pain hypersensitivity in mice. J Clin Invest. 2009 Feb; 119(2):287-94.
  19. Griffin RS, Costigan M, Brenner GJ, Ma CH, Scholz J, Moss A, Allchorne AJ, Stahl GL, Woolf CJ. Complement induction in spinal cord microglia results in anaphylatoxin C5a-mediated pain hypersensitivity. J Neurosci. 2007 Aug 8; 27(32):8699-708.
  20. Lötsch J, Belfer I, Kirchhof A, Mishra BK, Max MB, Doehring A, Costigan M, Woolf CJ, Geisslinger G, Tegeder I. Reliable screening for a pain-protective haplotype in the GTP cyclohydrolase 1 gene (GCH1) through the use of 3 or fewer single nucleotide polymorphisms. Clin Chem. 2007 Jun; 53(6):1010-5.
  21. Amaya F, Wang H, Costigan M, Allchorne AJ, Hatcher JP, Egerton J, Stean T, Morisset V, Grose D, Gunthorpe MJ, Chessell IP, Tate S, Green PJ, Woolf CJ. The voltage-gated sodium channel Na(v)1.9 is an effector of peripheral inflammatory pain hypersensitivity. J Neurosci. 2006 Dec 13; 26(50):12852-60.
  22. Tegeder I, Costigan M, Griffin RS, Abele A, Belfer I, Schmidt H, Ehnert C, Nejim J, Marian C, Scholz J, Wu T, Allchorne A, Diatchenko L, Binshtok AM, Goldman D, Adolph J, Sama S, Atlas SJ, Carlezon WA, Parsegian A, Lötsch J, Fillingim RB, Maixner W, Geisslinger G, Max MB, Woolf CJ. GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. Nat Med. 2006 Nov; 12(11):1269-77.
  23. Costigan M, Samad TA, Allchorne A, Lanoue C, Tate S, Woolf CJ. High basal expression and injury-induced down regulation of two regulator of G-protein signaling transcripts, RGS3 and RGS4 in primary sensory neurons. Mol Cell Neurosci. 2003 Sep; 24(1):106-16.
  24. Griffin RS, Mills CD, Costigan M, Woolf CJ. Exploiting microarrays to reveal differential gene expression in the nervous system. Genome Biol. 2003; 4(2):105.
  25. Costigan M, Befort K, Karchewski L, Griffin RS, D'Urso D, Allchorne A, Sitarski J, Mannion JW, Pratt RE, Woolf CJ. Replicate high-density rat genome oligonucleotide microarrays reveal hundreds of regulated genes in the dorsal root ganglion after peripheral nerve injury. BMC Neurosci. 2002 Oct 25; 3:16.
  26. Costigan M, Woolf CJ. No DREAM, No pain. Closing the spinal gate. Cell. 2002 Feb 8; 108(3):297-300.
  27. Benn SC, Costigan M, Tate S, Fitzgerald M, Woolf CJ. Developmental expression of the TTX-resistant voltage-gated sodium channels Nav1.8 (SNS) and Nav1.9 (SNS2) in primary sensory neurons. J Neurosci. 2001 Aug 15; 21(16):6077-85.
  28. Befort K, Costigan M, Woolf CJ. Differential gene expression--how to find new analgesic targets. Curr Opin Investig Drugs. 2001 Mar; 2(3):396-8.
  29. Delany NS, Hurle M, Facer P, Alnadaf T, Plumpton C, Kinghorn I, See CG, Costigan M, Anand P, Woolf CJ, Crowther D, Sanseau P, Tate SN. Identification and characterization of a novel human vanilloid receptor-like protein, VRL-2. Physiol Genomics. 2001 Jan 19; 4(3):165-74.
  30. Costigan M, Woolf CJ. Pain: molecular mechanisms. J Pain. 2000 Sep; 1(3 Suppl):35-44.
  31. Amaya F, Decosterd I, Samad TA, Plumpton C, Tate S, Mannion RJ, Costigan M, Woolf CJ. Diversity of expression of the sensory neuron-specific TTX-resistant voltage-gated sodium ion channels SNS and SNS2. Mol Cell Neurosci. 2000 Apr; 15(4):331-42.
  32. Lewis SE, Mannion RJ, White FA, Coggeshall RE, Beggs S, Costigan M, Martin JL, Dillmann WH, Woolf CJ. A role for HSP27 in sensory neuron survival. J Neurosci. 1999 Oct 15; 19(20):8945-53.
  33. Mannion RJ, Costigan M, Decosterd I, Amaya F, Ma QP, Holstege JC, Ji RR, Acheson A, Lindsay RM, Wilkinson GA, Woolf CJ. Neurotrophins: peripherally and centrally acting modulators of tactile stimulus-induced inflammatory pain hypersensitivity. Proc Natl Acad Sci U S A. 1999 Aug 3; 96(16):9385-90.
  34. Woolf CJ, Costigan M. Transcriptional and posttranslational plasticity and the generation of inflammatory pain. Proc Natl Acad Sci U S A. 1999 Jul 6; 96(14):7723-30.
  35. Tate S, Benn S, Hick C, Trezise D, John V, Mannion RJ, Costigan M, Plumpton C, Grose D, Gladwell Z, Kendall G, Dale K, Bountra C, Woolf CJ. Two sodium channels contribute to the TTX-R sodium current in primary sensory neurons. Nat Neurosci. 1998 Dec; 1(8):653-5.
  36. Costigan M, Mannion RJ, Kendall G, Lewis SE, Campagna JA, Coggeshall RE, Meridith-Middleton J, Tate S, Woolf CJ. Heat shock protein 27: developmental regulation and expression after peripheral nerve injury. J Neurosci. 1998 Aug 1; 18(15):5891-900.
  37. Costigan M, Chambers DA, Boot-Handford RP. Collagen turnover in renal disease. Exp Nephrol. 1995 Mar-Apr; 3(2):114-21.
  38. Sorge RE, Trang T, Dorfman R, Smith SB, Beggs S, Ritchie J, Austin JS, Zaykin DV, Vander Meulen H, Costigan M, Herbert TA, Yarkoni-Abitbul M, Tichauer D, Livneh J, Gershon E, Zheng M, Tan K, John SL, Slade GD, Jordan J, Woolf CJ, Peltz G, Maixner W, Diatchenko L, Seltzer Z, Salter MW, Mogil JS. Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. Nat Med. 2012 Mar 25; 18(4):595-9.
  39. del Camino D, Murphy S, Heiry M, Barrett LB, Earley TJ, Cook CA, Petrus MJ, Zhao M, D'Amours M, Deering N, Brenner GJ, Costigan M, Hayward NJ, Chong JA, Fanger CM, Woolf CJ, Patapoutian A, Moran MM. TRPA1 contributes to cold hypersensitivity. J Neurosci. 2010 Nov 10; 30(45):15165-74.
  40. Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci. 2009; 32:1-32.
  41. Moss A, Beggs S, Vega-Avelaira D, Costigan M, Hathway GJ, Salter MW, Fitzgerald M. Spinal microglia and neuropathic pain in young rats. Pain. 2007 Apr; 128(3):215-24.
  42. Mills C, Makwana M, Wallace A, Benn S, Schmidt H, Tegeder I, Costigan M, Brown RH, Raivich G, Woolf CJ. Ro5-4864 promotes neonatal motor neuron survival and nerve regeneration in adult rats. Eur J Neurosci. 2008 Feb; 27(4):937-46.
  43. Antoniades C, Shirodaria C, Van Assche T, Cunnington C, Tegeder I, Lötsch J, Guzik TJ, Leeson P, Diesch J, Tousoulis D, Stefanadis C, Costigan M, Woolf CJ, Alp NJ, Channon KM. GCH1 haplotype determines vascular and plasma biopterin availability in coronary artery disease effects on vascular superoxide production and endothelial function. J Am Coll Cardiol. 2008 Jul 8; 52(2):158-65.
  44. Mills CD, Allchorne AJ, Griffin RS, Woolf CJ, Costigan M. GDNF selectively promotes regeneration of injury-primed sensory neurons in the lesioned spinal cord. Mol Cell Neurosci. 2007 Oct; 36(2):185-94.
  45. Neely GG, Hess A, Costigan M, Keene AC, Goulas S, Langeslag M, Griffin RS, Belfer I, Dai F, Smith SB, Diatchenko L, Gupta V, Xia CP, Amann S, Kreitz S, Heindl-Erdmann C, Wolz S, Ly CV, Arora S, Sarangi R, Dan D, Novatchkova M, Rosenzweig M, Gibson DG, Truong D, Schramek D, Zoranovic T, Cronin SJ, Angjeli B, Brune K, Dietzl G, Maixner W, Meixner A, Thomas W, Pospisilik JA, Alenius M, Kress M, Subramaniam S, Garrity PA, Bellen HJ, Woolf CJ, Penninger JM. A genome-wide Drosophila screen for heat nociception identifies a2d3 as an evolutionarily conserved pain gene. Cell. 2010 Nov 12; 143(4):628-38.
  46. Moss A, Ingram R, Koch S, Theodorou A, Low L, Baccei M, Hathway GJ, Costigan M, Salton SR, Fitzgerald M. Origins, actions and dynamic expression patterns of the neuropeptide VGF in rat peripheral and central sensory neurones following peripheral nerve injury. Mol Pain. 2008 Dec 10; 4:62.
  47. Costigan M, Moss A, Latremoliere A, Johnston C, Verma-Gandhu M, Herbert TA, Barrett L, Brenner GJ, Vardeh D, Woolf CJ, Fitzgerald M. T-cell infiltration and signaling in the adult dorsal spinal cord is a major contributor to neuropathic pain-like hypersensitivity. J Neurosci. 2009 Nov 18; 29(46):14415-22.
  48. Ma CH, Brenner GJ, Omura T, Samad OA, Costigan M, Inquimbert P, Niederkofler V, Salie R, Sun CC, Lin HY, Arber S, Coppola G, Woolf CJ, Samad TA. The BMP coreceptor RGMb promotes while the endogenous BMP antagonist noggin reduces neurite outgrowth and peripheral nerve regeneration by modulating BMP signaling. J Neurosci. 2011 Dec 14; 31(50):18391-400.
  49. Latremoliere A, Latini A, Andrews N, Cronin SJ, Fujita M, Gorska K, Hovius R, Romero C, Chuaiphichai S, Painter M, Miracca G, Babaniyi O, Remor AP, Duong K, Riva P, Barrett LB, Ferreirós N, Naylor A, Penninger JM, Tegeder I, Zhong J, Blagg J, Channon KM, Johnsson K, Costigan M, Woolf CJ. Reduction of Neuropathic and Inflammatory Pain through Inhibition of the Tetrahydrobiopterin Pathway. Neuron. 2015 Jun 17; 86(6):1393-406.
  50. Tedeschi A, Omura T, Costigan M. CNS repair and axon regeneration: Using genetic variation to determine mechanisms. Exp Neurol. 2016 May 06.
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