- SCoBIRC BBSRB 483
- 741 S. Limestone
- Lexington, KY 40536-0509
859-323-1440 (University of Kentucky)
Fax: (859) 257-9372
B.S. in Neuroscience, Texas Christian University (1980);
Ph.D. in Physiological Psychology, State University of New York at Binghamton (1984);
Postdoctoral training at University of Rochester Medical School (1984-1988);
Mitochondrial Function, microRNA Activity and Cell Death in Traumatic Brain Injury
It has been well documented that widespread neuronal and glial cell death occurs following traumatic spinal cord and brain injury. In addition, important advances have been made in understanding the intracellular pathways controlling cell death after injury. The goal of our research is to limit cell loss and the resulting neurological deficits by blocking steps occurring early in the cell death process. Recently, we have focused our efforts on identifying the mitochondrial events responsible for regulating cell survival and death. Our current studies have revealed a novel role for mitochondria in the regulation of cellular miRNA activity. In particular, we have observed that TBI results in a compartmental shift of miRNAs regulating macrophage phenotype. One such miRNA is miR-146a, which tagets TRAF6 and IRAK1 and downregulates markers of the M1 pro-inflammatory macrophage phenotype. We are pursuing cell delivery strategies to introduce miR-146a particularly interested in identifying therapeutic agents/strategies that limit mitochondrial dysfunction as a means of promoting cell survival.
Mitochondrial Function, microRNA (miRNA) Activity and Cell Death in Traumatic Brain Injury-
The goal of our research is to limit cell loss and the resulting neurological deficits following CNS injury by targeting steps occurring early in the cell death process. Recently, we have focused our efforts on identifying the mitochondrial events responsible for regulating cell survival and death. Our current studies have revealed a novel role for mitochondria in the regulation of cellular miRNA activity. In particular, we have observed that traumatic brain injury results in a compartmental shift of miRNAs regulating inflammation and in particular, macrophage phenotype. One such miRNA is miR-146a, which targets TRAF6 and IRAK1 and down-regulates markers of the M1 pro-inflammatory macrophage phenotype while facilitating expression of the anti-inflammatory M2 phenotype. We are now pursuing cell delivery strategies to introduce miR-146a to the injured brain as a way of promoting expression of the reparative anti-inflammatory M2 macrophage phenotype. These novel studies are being conducted by Dr. Wangxia Wang and Dr. Paresh Prajapati.
Wang-Xia Wang, Ph.D. Scientist III
Paresh Prajapati, Ph.D. Postdoc
Springer, J.E., Visavadiya, N.P., Sullivan, P.G., and Hall, E.D. Post-injury treatment with NIM811 promotes recovery of bladder function and tissue sparing in adult female rats following spinal cord contusion: A dose-response study. Accepted in Journal of Neurotrauma
Raut, N., Springer, J.E., Salles, S.S. and Nagar, V.R. Functional improvement in spinal abscess patients with and without a history of intravenous substance abuse. In press, AAPMR Journal
Wang, W.X., Sullivan, P.G., and Springer, J.E. Mitochondria and microRNA crosstalk in traumatic brain injury. Prog Neuropsychopharmacol Biol Psychiatry. Feb 6;73:104-108, 2017.
Visavadiya, N.P. and Springer, J.E. Altered cerebellar circuitry following thoracic spinal cord injury in adult rats. Neural Plasticity, Volume 2016, Article ID 8181393, http://dx.doi.org/10.1155/2016/8181393, 2016.
Wang, W.X. and Springer, J.E. Role of mitochondria in regulating miRNA activity and its relevance to the central nervous system. Neural Regeneration Research 10(7):1026-1028, 2015.
Nagar, V.R., Springer, J.E., and Salles, S.S. Increased incidence of spinal abscess and drug abuse after implementation of strict state controlled substances prescription drug abuse legislation. Pain Medicine 16:2031-2035, 2015.
*Wang, W.X., Visavadiya, N.P., Pandya, J., Nelson, P.T., Sullivan, P.G., and Springer, J.E. Identification and response to of mitochondria-associated miRNA in rat hippocampus following traumatic brain injury. Exp. Neurol. 265:84-93, 2015. (*most viewed Experimental Neurology publication in 2015).
Chen A, Sun S, Ravikumar R, Visavadiya NP, Springer JE. Differential proteomic analysis of acute contusive spinal cord injury in rats using iTRAQ reagent labeling and LC-MS/MS. Neurochem Res. 2013 Nov;38(11):2247-55. doi: 10.1007/s11064-013-1132-y. Epub 2013 Aug 21. PubMed PMID: 23963509.
Readnower RD, Pandya JD, McEwen ML, Pauly JR, Springer JE, Sullivan PG. Post-injury administration of the mitochondrial permeability transition pore inhibitor, NIM811, is neuroprotective and improves cognition after traumatic brain injury in rats. J Neurotrauma. 2011 Sep;28(9):1845-53. doi: 10.1089/neu.2011.1755. Epub 2011 Aug 29. PubMed PMID: 21875332; PubMed Central PMCID: PMC3172877.
Rabchevsky AG, Patel SP, Springer JE. Pharmacological interventions for spinal cord injury: where do we stand? How might we step forward? Pharmacol Ther. 2011 Oct;132(1):15-29. doi: 10.1016/j.pharmthera.2011.05.001. Epub 2011 May 14. Review. PubMed PMID: 21605594.
McEwen ML, Sullivan PG, Rabchevsky AG, Springer JE. Targeting mitochondrial function for the treatment of acute spinal cord injury. Neurotherapeutics. 2011 Apr;8(2):168-79. doi: 10.1007/s13311-011-0031-7. Review. PubMed PMID: 21360236; PubMed Central PMCID: PMC3101832.
Chen A, McEwen ML, Sun S, Ravikumar R, Springer JE. Proteomic and phosphoproteomic analyses of the soluble fraction following acute spinal cord contusion in rats. J Neurotrauma. 2010 Jan;27(1):263-74. doi: 10.1089/neu.2009.1051. PubMed PMID: 19691422; PubMed Central PMCID: PMC2864456.
Mbye LH, Singh IN, Sullivan PG, Springer JE, Hall ED. Attenuation of acute mitochondrial dysfunction after traumatic brain injury in mice by NIM811, a non-immunosuppressive cyclosporin A analog. Exp Neurol. 2008 Jan;209(1):243-53. Epub 2007 Oct 5. PubMed PMID: 18022160.
Ravikumar R, McEwen ML, Springer JE. Post-treatment with the cyclosporin derivative, NIM811, reduced indices of cell death and increased the volume of spared tissue in the acute period following spinal cord contusion. J Neurotrauma. 2007 Oct;24(10):1618-30. PubMed PMID: 17970625.
McEwen ML, Sullivan PG, Springer JE. Pretreatment with the cyclosporin derivative, NIM811, improves the function of synaptic mitochondria following spinal cord contusion in rats. J Neurotrauma. 2007 Apr;24(4):613-24. PubMed PMID: 17439345.