Wikipedia

Sandra M. Garraway

Sandra M. Garraway is a Canadian-American neuroscientist and assistant professor of physiology in the Department of Physiology at Emory University School of Medicine in Atlanta, Georgia. Garraway is the director of the Emory Multiplex Immunoassay Core (EMIC) where she assists researchers from both academia and industry to perform, analyze, and interpret their multiplexed immunoassays. Garraway studies the neural mechanisms of spinal nociceptive pain after spinal cord injury and as a postdoctoral researcher she discovered roles for both BDNF and ERK2 in pain sensitization and developed novel siRNA technology to inhibit ERK2 as a treatment for pain.

Sandra M. Garraway
NationalityCanadian
Alma materUniversity of Guelph
University of Manitoba
Stony Brook University
Weill Cornell Medical College
Known forRole of BDNF and ERK2 in pain sensitization in the spinal cord
AwardsDepartment of Defense Congressional Directed Medical Research Programs Award
Scientific career
FieldsNeuroscience
InstitutionsEmory University School of Medicine

Early life and education edit

Garraway pursued her Bachelors of Arts at the University of Guelph, in Guelph, Ontario, Canada.[1] She graduated in 1993 and moved to Mantioba where she pursued her graduate studies at the University of Manitoba, in Winnipeg, Manitoba, Canada.[2] She studied under the mentorship of Shawn Hochman in the Department of Physiology exploring synaptic plasticity in deep dorsal horn (DDH) neurons since they play a fundamental role in nociception and relaying pain information to the brain.[3] Garraway published four first-author papers during her PhD.[4]

Mechanisms of plasticity in deep dorsal horn neurons edit

Garraway explored how primary afferent stimulation impacted plasticity, in the form of long term potentiation (LTP) or long term depression (LTD), of the DDH neurons.[5] LTP and LTD had only just been identified in the spinal cord, and Garraway discovered that LTP and LTD can also be induced in the DDH neurons with even lower frequency afferent stimulation.[5] She also found that in rats aged P9-16, only LTP could be produced.[5] These findings shed light on potential mechanisms of prolonged pain sensation, or chronic pain, as LTD and LTP present forms of long lasting cellular memory.[5] Garraway then explored the descending serotonergic projections that modulate the DDH neurons.[6] She used an in vitro slice preparation of DDH neurons and applied various serotonin receptor ligands to assess the effects of modulation at each serotonin receptor subtype in the primary afferent neurons.[6] She found that the afferents are in fact modulated by several serotonin receptors and that 5-HT1A modulation facilitates evoked responses whereas 5-HT7 depressed evoked responses.[6] Her work was one of the first identifications of the presence and effects of 5-HT7 receptors in the spinal cord and her results showed promise in using selective serotonin receptor targeting in the modulation of pain.[6] Garraway then further characterized monoamine transmitter effects in the spinal cord in comparison with the actions of acetylcholine.[7] She found dopamine, serotonin, and norepinephrine depressed postsynaptic potentials and did not modify the passive membrane properties of neurons whereas acetylcholine lead to increased EPSP amplitude.[7] Further, Garraway found that the addition of both serotonin and norepinephrine simultaneously could evoke even greater depression than either in isolation.[7]

BDNF and sensitization edit

After completing her graduate studies in 2000, Garraway moved to the United States to pursue her postdoctoral training at the State University of New York at Stony Brook.[8] Studying under Lorne Mendell, she explored the implications of brain-derived neurotrophic factor (BDNF) on central sensitization and exaggerated pain states.[9] Garraway found that BDNF signalling in the dorsal horn led to facilitation, and the initiation of this facilitation was dependent on NMDA receptor signalling and phospholipase C.[9] Garraway then explored how spinal injury impacted the effects of BDNF on lamina II neurons.[10] She found that after neonatal spinal injury, BDNF was no longer able to facilitate dorsal-root EPSCs.[10] After discovering that NMDA receptor dysfunction was not the cause for decreased responses, she elucidated that expression of dysfunctional trkB might be contributing to the decline in BDNF effects after injury.[10]

Garraway then completed a second postdoctoral fellowship in New York City, at the Weill Cornell Medical College.[8] She worked in the Department of Pharmacology and became an instructor of Pharmacology as well. Garraway studied under the mentorship of Charles Inturrisi, exploring methods of chronic pain management and biological mechanisms of pain with which to target.[3] She first designed and tested a novel small interfering RNA that knocked down expression of the NR1 subunit of the NMDA receptor.[11] This led to decreased mechanical allodynia after injection of an inflammatory agent.[11] She then tested the efficacy of the siRNA on formalin-induced phase 2 nociceptive responses, and it was able to significantly reduce them.[12] Both of her results show that vector-derived siRNAs targeting the NR1 subunit of the AMPA receptor might be beneficial in the treatment of pain by reducing expression of genes mediating pain sensation in the spinal cord.[12]

Career and research edit

In 2008, Garraway moved to Texas A & M University where she became a Research Assistant Professor and worked with James W. Grau exploring the neurobiological underpinnings of learned pain in the spinal cord.[13] In 2014, Garraway was recruited to Emory University where she was appointed to Assistant Professor of Physiology at the School of Medicine. Garraway is also a Faculty Member for the Neuroscience Graduate Program at Emory.[2] In 2019, she was promoted to Scientific Director of the Emory Multiplex Immunoassay Core, where she now guides researchers in both academia and industry in the use of facility equipment and analysis and interpretation of the results of multiplexed immunoassays.

In addition to her role as Scientific Core Director, Garraway is also the Principal Investigator of the Garraway Lab which explores the mechanisms underlying the development of chronic pain after spinal cord injury.[2] Her lab uses peripheral and spinal cord injury models to explore cellular mechanisms of neuropathic pain, how autonomic dysfunction is related to sensitization, and how peripheral and central pain networks interact to lead to chronic pain.[14] The Garraway Lab is funded by the Craig Neilsen Foundation,[15] the National Institutes of Health,[16] and the Department of Defense.[17]

Garraway is also a member of various national and international groups working to study pain and find cures and treatments for pain disorders. Garraway is a member of the International Pain Research Forum[18] and is also a member of The Institute for Rehabilitation and Research (TIRR) Foundation[19] a collaborative research foundation that innovates therapies for people with sustained nervous system damage.

Role of BDNF in pain sensitization edit

After discovering a role for spinal cord BDNF signaling in pain sensitization in her postdoc, Garraway explored whether the behavioral correlates of pain were associated with cellular changes mediated by BDNF.[20] She found that nociceptive stimulation decreased expression of BDNF, TrkB, and ERK2 in the dorsal spinal cord.[20] Garraway and her colleagues then found that BDNF signalling mediates the protective and restorative effects of instrumental training in models where pain is controllable.[21] After instrumental training, where rats learned to not flex their hind limb to prevent pain, there were increases in BDNF and increased plasticity. Further, when BDNF was injected during uncontrollable pain stimulation, it blocked allodynia and enabled rats to learn to not extend their hind legs.[21] Overall, her results and work point to the importance of BDNF in beneficial plasticity in pain models and the potential importance of BDNF in plasticity and recovery after spinal cord injury.[21]

Role of TNF alpha in chronic pain edit

Garraway also explores the role of Tumor Necrosis Factor alpha (TNFa) signalling in the development and maintenance of chronic pain.[22] In 2015, she discovered increases in TNFa expression after nociceptive stimulation post spinal cord injury and that downstream TNFa signalling may induce apoptosis in neurons and microglia.[22]  In 2019, Garraway and her colleagues found that peripheral inflammation increases the onset of mechanical hypersensitivity after spinal cord injury and that TNFa is involved in the early onset sensitization process.[23]

Awards and honors edit

  • 2015 Department of Defense Congressional Directed Medical Research Programs Award[17]
  • 2014 Mission Connect Grant - The Institute for Rehabilitation Research

Select publications edit

  • Grau JW, Huang YJ, Turtle JD, et al. When Pain Hurts: Nociceptive Stimulation Induces a State of Maladaptive Plasticity and Impairs Recovery after Spinal Cord Injury. J Neurotrauma. 2017;34(10):1873‐1890. doi:10.1089/neu.2016.4626[24]
  • Martin KK, Parvin S, Garraway SM. Peripheral Inflammation Accelerates the Onset of Mechanical Hypersensitivity after Spinal Cord Injury and Engages Tumor Necrosis Factor α Signaling Mechanisms. J Neurotrauma. 2019;36(12):2000‐2010. doi:10.1089/neu.2018.5953[23]
  • Garraway SM, Huie JR. Spinal Plasticity and Behavior: BDNF-Induced Neuromodulation in Uninjured and Injured Spinal Cord. Neural Plast. 2016;2016:9857201. doi:10.1155/2016/9857201[25]
  • Garraway SM, Woller SA, Huie JR, et al. Peripheral noxious stimulation reduces withdrawal threshold to mechanical stimuli after spinal cord injury: role of tumor necrosis factor alpha and apoptosis. Pain. 2014;155(11):2344‐2359. doi:10.1016/j.pain.2014.08.034[22]
  • Garraway SM, Turtle JD, Huie JR, et al. Intermittent noxious stimulation following spinal cord contusion injury impairs locomotor recovery and reduces spinal brain-derived neurotrophic factor-tropomyosin-receptor kinase signaling in adult rats. Neuroscience. 2011;199:86‐102. doi:10.1016/j.neuroscience.2011.10.007[20]
  • Garraway SM, Xu Q, Inturrisi CE. siRNA-mediated knockdown of the NR1 subunit gene of the NMDA receptor attenuates formalin-induced pain behaviors in adult rats. J Pain. 2009;10(4):380‐390. doi:10.1016/j.jpain.2008.09.013[12]
  • Garraway SM, Xu Q, Inturrisi CE. Design and evaluation of small interfering RNAs that target expression of the N-methyl-D-aspartate receptor NR1 subunit gene in the spinal cord dorsal horn. J Pharmacol Exp Ther. 2007;322(3):982‐988. doi:10.1124/jpet.107.123125[11]
  • Garraway SM, Petruska JC, Mendell LM. BDNF sensitizes the response of lamina II neurons to high threshold primary afferent inputs. Eur J Neurosci. 2003;18(9):2467‐2476. doi:10.1046/j.1460-9568.2003.02982.x[9]
  • Garraway SM, Hochman S. Modulatory actions of serotonin, norepinephrine, dopamine, and acetylcholine in spinal cord deep dorsal horn neurons. J Neurophysiol. 2001;86(5):2183‐2194. doi:10.1152/jn.2001.86.5.2183[7]
  • Garraway SM, Hochman S. Pharmacological characterization of serotonin receptor subtypes modulating primary afferent input to deep dorsal horn neurons in the neonatal rat. Br J Pharmacol. 2001;132(8):1789‐1798. doi:10.1038/sj.bjp.0703983[6]
  • Garraway SM, Pockett S, Hochman S. Primary afferent-evoked synaptic plasticity in deep dorsal horn neurons from neonatal rat spinal cord in vitro. Neurosci Lett. 1997;230(1):61‐64. doi:10.1016/s0304-3940(97)00475-8[5]

References edit

  1. ^ "Guelph Alumnus Magazine, Fall 1996 - [PDF Document]". fdocuments.us. Retrieved 2020-06-16.
  2. ^ a b c "NS Faculty Member| GDBBS | Emory University". biomed.emory.edu. Retrieved 2020-06-16.
  3. ^ a b "Shawn Hochman - Publications". neurotree.org. Retrieved 2020-06-16.
  4. ^ "Sandra Garraway - Publications". neurotree.org. Retrieved 2020-06-16.
  5. ^ a b c d e Garraway, Sandra M; Pockett, Susan; Hochman, Shawn (1997-07-11). "Primary afferent-evoked synaptic plasticity in deep dorsal horn neurons from neonatal rat spinal cord in vitro". Neuroscience Letters. 230 (1): 61–64. doi:10.1016/S0304-3940(97)00475-8. ISSN 0304-3940. PMID 9259464. S2CID 33923901.
  6. ^ a b c d e Garraway, S. M.; Hochman, S. (April 2001). "Pharmacological characterization of serotonin receptor subtypes modulating primary afferent input to deep dorsal horn neurons in the neonatal rat". British Journal of Pharmacology. 132 (8): 1789–1798. doi:10.1038/sj.bjp.0703983. ISSN 0007-1188. PMC 1572723. PMID 11309251.
  7. ^ a b c d Garraway, Sandra M.; Hochman, Shawn (2001-11-01). "Modulatory Actions of Serotonin, Norepinephrine, Dopamine, and Acetylcholine in Spinal Cord Deep Dorsal Horn Neurons". Journal of Neurophysiology. 86 (5): 2183–2194. doi:10.1152/jn.2001.86.5.2183. ISSN 0022-3077. PMID 11698510. S2CID 50065.
  8. ^ a b "Sandra M. Garraway, PhD". www.physiology.emory.edu. Retrieved 2020-06-16.
  9. ^ a b c Garraway, Sandra M.; Petruska, Jeffrey C.; Mendell, Lorne M. (November 2003). "BDNF sensitizes the response of lamina II neurons to high threshold primary afferent inputs". The European Journal of Neuroscience. 18 (9): 2467–2476. doi:10.1046/j.1460-9568.2003.02982.x. ISSN 0953-816X. PMID 14622147. S2CID 40287969.
  10. ^ a b c Garraway, Sandra M.; Anderson, Aileen J.; Mendell, Lorne M. (September 2005). "BDNF-induced facilitation of afferent-evoked responses in lamina II neurons is reduced after neonatal spinal cord contusion injury". Journal of Neurophysiology. 94 (3): 1798–1804. doi:10.1152/jn.00179.2005. ISSN 0022-3077. PMID 15901762.
  11. ^ a b c Garraway, Sandra M.; Xu, Qinghao; Inturrisi, Charles E. (September 2007). "Design and evaluation of small interfering RNAs that target expression of the N-methyl-D-aspartate receptor NR1 subunit gene in the spinal cord dorsal horn". The Journal of Pharmacology and Experimental Therapeutics. 322 (3): 982–988. doi:10.1124/jpet.107.123125. ISSN 0022-3565. PMID 17551091. S2CID 10718252.
  12. ^ a b c Garraway, Sandra M.; Xu, Qinghao; Inturrisi, Charles E. (April 2009). "siRNA-mediated knockdown of the NR1 subunit gene of the NMDA receptor attenuates formalin-induced pain behaviors in adult rats". The Journal of Pain. 10 (4): 380–390. doi:10.1016/j.jpain.2008.09.013. ISSN 1528-8447. PMC 2699265. PMID 19185544.
  13. ^ "NEUROSCIENCE - TEXAS A&M UNIVERSITY". Ciencia Puerto Rico. 2011-09-28. Retrieved 2020-06-16.
  14. ^ "Our Research - Garraway Lab". Emory University School of Medicine. Retrieved 8 August 2021.
  15. ^ "Continuous sensor-based homecage recordings for SCI research - CHN Widget". chn.dimensions.ai. Retrieved 8 August 2021.
  16. ^ "Peripheral BDNF drives primary afferent hyperexcitability and pain hypersensitivity". reporter.nih.gov. National Institute of Health. Retrieved 8 August 2021.
  17. ^ a b "Electrophysiological and Behavioral Evaluation of C-LTMR Plasticity Induced by Spinal Cord Injury: Transformation from Pleasure to Pain Afferents". Congressionally Directed Medical Research Programs (CDMRP). Retrieved 2020-06-16.
  18. ^ "| Pain Research Forum". www.painresearchforum.org. Retrieved 2020-06-16.
  19. ^ "TIRR Foundation Members". tirrfoundation.org. Retrieved June 14, 2020.
  20. ^ a b c Garraway, S. M.; Turtle, J. D.; Huie, J. R.; Lee, K. H.; Hook, M. A.; Woller, S. A.; Grau, J. W. (2011-12-29). "Intermittent noxious stimulation following spinal cord contusion injury impairs locomotor recovery and reduces spinal brain-derived neurotrophic factor-tropomyosin-receptor kinase signaling in adult rats". Neuroscience. 199: 86–102. doi:10.1016/j.neuroscience.2011.10.007. ISSN 1873-7544. PMC 3237800. PMID 22027236.
  21. ^ a b c Huie, J. R.; Garraway, S. M.; Baumbauer, K. M.; Hoy, K. C.; Beas, B. S.; Montgomery, K. S.; Bizon, J. L.; Grau, J. W. (2012-01-03). "Brain-derived neurotrophic factor promotes adaptive plasticity within the spinal cord and mediates the beneficial effects of controllable stimulation". Neuroscience. 200: 74–90. doi:10.1016/j.neuroscience.2011.10.028. ISSN 1873-7544. PMC 3249495. PMID 22056599.
  22. ^ a b c Garraway, Sandra M.; Woller, Sarah A.; Huie, J. Russell; Hartman, John J.; Hook, Michelle A.; Miranda, Rajesh C.; Huang, Yung-Jen; Ferguson, Adam R.; Grau, James W. (November 2014). "Peripheral noxious stimulation reduces withdrawal threshold to mechanical stimuli after spinal cord injury: role of tumor necrosis factor alpha and apoptosis". Pain. 155 (11): 2344–2359. doi:10.1016/j.pain.2014.08.034. ISSN 1872-6623. PMC 4253555. PMID 25180012.
  23. ^ a b Martin, Karmarcha K.; Parvin, Shangrila; Garraway, Sandra M. (15 June 2019). "Peripheral Inflammation Accelerates the Onset of Mechanical Hypersensitivity after Spinal Cord Injury and Engages Tumor Necrosis Factor α Signaling Mechanisms". Journal of Neurotrauma. 36 (12): 2000–2010. doi:10.1089/neu.2018.5953. ISSN 1557-9042. PMC 6599394. PMID 30520675.
  24. ^ Grau, James W.; Huang, Yung-Jen; Turtle, Joel D.; Strain, Misty M.; Miranda, Rajesh C.; Garraway, Sandra M.; Hook, Michelle A. (2017-05-15). "When Pain Hurts: Nociceptive Stimulation Induces a State of Maladaptive Plasticity and Impairs Recovery after Spinal Cord Injury". Journal of Neurotrauma. 34 (10): 1873–1890. doi:10.1089/neu.2016.4626. ISSN 0897-7151. PMC 5444485. PMID 27788626.
  25. ^ Garraway, Sandra M.; Huie, J. Russell (2016). "Spinal Plasticity and Behavior: BDNF-Induced Neuromodulation in Uninjured and Injured Spinal Cord". Neural Plasticity. 2016: 1–19. doi:10.1155/2016/9857201. ISSN 2090-5904. PMC 5046018. PMID 27721996.
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