The following are brief descriptions of the ongoing research projects conducted in our laboratory:
1. Glucocorticoid receptor, inflammation, and cell death: In collaboration with Chung Hsu at Washington University, St. Louis, we were among the first to identify apoptotic cell death following SCI. We systemically investigated inflammation cascades including the expression of TNFα, TNF receptors, and transcription factors NF-κB and AP-1. We investigated the expression and functional role of the glucocorticoids receptor (GR) in mediating the structural and functional outcomes after SCI. Both pharmacological and genetic approaches were used in these studies.
1. Liu XZ, Xu XM, Hu R, Cheng D, Zhang SX, McDonald JW, Dong HX, Wu YJ, Fan GS, Jacquin MF, Hsu CY, Choi DW (1997) Neuronal and glial apoptosis after traumatic spinal cord injury. J Neurosci 17:5395-5406.
2. Yan P, Xu J, Li Q, Chen SW, Kim G-M, Hsu CY, Xu XM (1999) Gluococorticoid receptor expression in the spinal cord after traumatic injury in adult rats. J Neurosci 19: 9355-9363.
3. Kim GM, Xu J, Xu J, Song S-K, Yan P, Ku G, Xu XM, Hsu CY (2001) Tumor necrosis factor receptor deletion reduces nuclear factor-kB activation, cellular inhibitor of apoptosis protein 2 expression, and functional recovery after traumatic spinal cord injury. J Neurosci 21:6617-6625.
4. Xu J, G-M Kim, Ahmed SH, Xu J, Yan P, Xu XM, Hsu CY (2001) Glucocorticoid receptor-mediated suppression of AP-1 activation and matrix metalloproteinase expression after spinal cord injury. J Neurosci 21:92-97.
2. Phospholipase A2 as a novel target for neuroprotection: Phospholipase A2 (PLA2) is a diverse family of lipolytic enzymes. We found that the total PLA2 activity and expression, as well as the expression of cytosolic PLA2 (cPLA2) and secretory PLA2-IIA (sPLA2-IIA), increased following SCI. Exogenous administration of PLA2 induced inflammatory, oxidation, motor dysfunction, and demyelination. Inhibition of PLA2 with annexin A1 (ANX-A1), a PLA2 inhibitor, in a rat SCI model showed inhibition of inflammation and neuroprotection. Currently, we are investigating whether PLA2 serves as a common pathway that mediates multiple injury mechanisms and whether blocking PLA2 can be an attractive strategy to improve tissue repair and functional recovery.
1. Liu N-K, Zhang YP, Titsworth WL, Jiang X, Han S, Lu PH, Shields CB and Xu X-M* (2006) A Novel Role of Phospholipase A2 in Mediating Spinal Cord Secondary Injury. Annal Neurol 59:606-619.
2. Titsworth WL, Cheng X, Ke Y, Deng L, Burckardt KA, Pendleton C, Liu N-K, Shao H, Cao Q-L, Xu X-M* (2009) Differential expression of sPLA2 following spinal cord injury and a functional role for sPLA2-IIA in mediating oligodendrocyte death. Glia 1521-1537. [PMID: 19306380]
3. Liu NK, Byers JS, Lam T, Lu Q, Sengelaub DR, Xu X-M* (2014) Inhibition of cPLA2 has neuroprotective effects on motoneuron and muscle atrophy following spinal cord injury J Neurotrauma Nov 11. [Epub ahead of print].
4. Liu N-K, Deng L-X, Zhang YP, Lu Q-B, Wang X-F, Hu J-G, Oakes E, Shields CB, Xu, X-M* (2014) cPLA2 protein as a novel therapeutic target for spinal cord injury Ann Neurol 75(5):644-58
3. Schwann cell transplantation: Working with Drs. Richard and Mary Bartlett Bunge, I was among the first to transplant Schwann cells (SCs) into the injured spinal cord to promote axonal regeneration following spinal cord injury (SCI). This earlier work, along with others, provided the scientific rationale for the clinical trial of autologous SC transplantation in human SCI patients being conducted at the Miami Project to Cure Paralysis, University of Miami. Currently, my laboratory has been testing combinatorial strategies involving SC transplantation, delivery of trophic factors, and removal of glial scar to enhance the survival, regeneration, and recovery of function in animal models of SCI and to translate these strategies to pre-clinical settings.
1. Xu XM, Guénard V, Kleitman N, and Bunge MB (1995a) Axonal regeneration into Schwann cell-seeded guidance channels grafted into transected adult rat spinal cord. J Comp Neurol 351:145-160.
2. Xu XM, Guénard V, Kleitman N, Bunge MB (1995b) A combination of BDNF and NT-3 promotes supraspinal axonal regeneration into Schwann cell grafts in adult rat thoracic spinal cord. Exp Neurol 134:261-272.
3. Zhang L, Ma Z, Smith GM, Wen X, Pressman Y, Wood PM, Xu X-M* (2009) GDNF-enhanced axonal regeneration and myelination following spinal cord injury is mediated by primary effects on neurons. Glia 57:1178-1191.
4. Deng L, Deng P, Ruan Y, Xu ZC, Liu N, Wen X, Smith GM, Xu X-M* (2013) A novel growth-promoting pathway formed by GDNF-overexpressing Schwann cells promotes propriospinal axonal regeneration, synapse formation, and partial recovery of function after spinal cord injury. J Neurosci 33:5655-5667.
4. Corticospinal regeneration: The corticospinal tract (CST) is one of the main motor pathways of the spinal cord and is particularly important for hand function. A major effort in my laboratory is to promote corticospinal regeneration/plasticity after various treatments. Two major strategies were tested: 1) inhibition of conventional protein kinases C (PKC) at the lesion site and motor cortex (In collaboration with Dr. Zhigang He at Harvard Medical School), and 2) inhibition of Wnt signaling (In collaboration with Dr. Yimin Zou at UCSD). Both strategies yielded promising results. We are now studying whether regeneration/plasticity of CST axons could form a new functional relay within the injured spinal cord to promote recovery of motor function.
1. Sivasankaran, R., Pei, J., Wang, K.C., Zhang, Y.P., Shields, C.B., Xu, X.-M.* and He, Z.* (2004) Protein kinase C mediates inhibitory effects of myelin and chondroitin sulfate proteoglycans on axonal regeneration. Nat Neurosci 7:261-268.
2. Liu Y, Wang X, Sherman R, Lu C-C, Steward O*, Xu X-M*, Zou Y* (2008) Repulsive Wnt signaling inhibits axon regeneration following central nervous system injury. J Neurosci 28:8376-8382.
3. Wang X, Hu J, She Y, Smith GM, Xu X-M* (2013) Cortical PKC inhibition promotes axonal regeneration of the corticospinal tract and forelimb recovery after cervical dorsal spinal hemisection in adult rats Cerebral Cortex. Advance Access Publication June 28, 2013; Printed Publication 24:3069-3079, 2014 [PMID: 23810979]
4. Al-Ali H, Ding Y, Slepak T, Wu W, Sun Y, Martinez Y, Xu X-M, Lemmon V*, Bixby J* (2017) The mTOR substrate S6 Kinase 1 (S6K1) is a negative regulator of axon regeneration and a potential drug target for Central Nervous System. J. Neurosci. 37:7079-7095. DOI: https://doi.org/10.1523/JNEUROSCI.0931-17.2017
5. Traumatic brain injury: As a Scientific Director of the Indiana Spinal Cord and Brain Injury Research Group (ISCBIRG), I also contribute to the TBI Consortium Group at IU School of Medicine by establishing several well-accepted models of TBI and by developing new TBI models for our own need. Using these models, we are currently studying 1) the role of cPLA2 in the TBI model, and 2) whether blocking PSD-95 and nNOS interaction results in neuroprotection (with Dr. Anantha Shekhar at IU School of Medicine).
1. Liu NK, Zhang Y-P, O’Connor J, Gianaris A, Oakes E, Lu Q-B, Verhovshek T, Walker C, Shields CB, Xu X-M* (2013) A bilateral head injury that shows graded brain damage and behavior deficits in adult mice Brain Research 1499:121-128 [PMID:23276498]
2. Liu N-K, Zhang Y-P, Zou J, Verhovshek T, Chen C, Lu Q-B, Walker CL, Shields BS, Xu X-M* (2014) A semicircular controlled cortical impact produces long-term motor and cognitive dysfunction that correlates well with damage to both the sensorimotor cortex and hippocampus. Brain Res 1576:18-26, 2014.
3. Wang H, Zhang YP, Cain J, Tuchek CA, Shields LBE, Shi R, Li J, Shields CB, Xu X-M* (2016) A Compact blast brain injury device produces graded injury severities, neuronal degeneration and functional deficits. J Neuropath Exp Neurol 271:368-378, 2016.
