Noreen Bukhari

3rd Year Graduate Student

Department: Pharmacological Sciences

Graduate Program: Neuroscience

Advisor: Styliani-Anna Tsirka

Abstract:

Title:  The Role of Tissue Plasminogen Activator in Axonal
Regeneration of a Mouse Spinal Cord Injury Model

The National Spinal Cord Injury Database estimates that 11,000 new cases of spinal cord injury (SCI) occur in the United States each year with a prevalence of 253,000 persons. Acute administration of corticosteroids to suppress the body’s inflammatory response is the most widely used medical treatment for SCI. This treatment highlights two important points for researchers: the body’s secondary response is the more debilitating effect of the injury and new therapeutic approaches must focus on treating the chronic form of the injury. Chondroitinase ABC (ChABC) is a bacterial enzyme that has consistently been shown to reduce the secondary damage called glial scar and enhance axonal plasticity. However, the mechanism underlying this repair remains unclear.

Our group has previously reported that ChABC enhances the interaction of the extracellular serine protease, tissue plasminogen activator (tPA) and its downstream product, plasmin, with the extracellular matrix molecules of the glial scar in in vitro and ex vivo models of SCI. We now test the contribution of this serine protease to ChABC promoted axonal repair using mice deficient in tPA. We hypothesized that tPA acts downstream of ChABC to promote axonal plasticity after SCI. We test the role of tPA in the survival and neurite outgrowth of primary cortical neurons in an in vitro ChABC treated glial scar. We also evaluate tPA's role as a downstream effector of ChABC action in an in vivo model of mouse SCI. Immunohistochemistry is used to visualize the glial scar and axon tracing to measure neurite outgrowth. These studies are intended to elucidate the mechanism of action of a leading therapy against spinal cord injury, and thereby help in the drug development of the bacterial compound.

Publications:
(MSTP-supported publications indicated with an *)

*Nolin W, Emmetsberger J, Bukhari N, Zhang Y, Levine J, Tsirka S. (2008). tPA-Mediated Generation of Plasmin is Catalyzed by the Proteoglycan NG2. GLIA. 56:177-189.

Olszewski RT, Bukhari N, Zhou J, Kozikowski AP, Wroblewski JT, Shamimi-Noori S, Wroblewska B, Bzdega T, Vicini S, Barton FB, Neale JH (2004). NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group mGluR. J Neurochem. 89(4):876-85.

Bacich DJ, Ramadan E, O’Keefe DS, Bukhari N, Wegozsewska I, Ojeifo O, Olszewski R, Wrenn CC, Bzdega T, Wroblewska B, Heston WD, Neale JH. (2002). Deletion of the glutamate carboxypeptidase II gene in mice reveals a second enzyme activity that hydrolyzes N-acetylaspartylglutamate. J Neurochem. 83(1):20-9.