Styliani-Anna E. Tsirka, PhD – Professor
Tissue Plasminogen Activator in the Mammalian Hippocampus Neuronal-microglial interactions
in the physiology and pathology of the central nervous system
Professor, Pharmacological Sciences
Ph.D., University of Thessaloniki, Greece
Postdoctorals, University of California, San Francisco
and SUNY at Stony Brook
stella@pharm.stonybrook.edu
4-3859
Proteases modulate neuronal cell structure and viability in the CNS. Tissue plasminogen activator (tPA) is an extracellular serine protease originally studied for its ability to dissolve thrombotic clots in the vascular system. tPA initiates a proteolytic cascade that ultimately mediates the degeneration of neuronal cells after experimental injury in the hippocampus. Mice lacking tPA are resistant to excitotoxin-induced neuronal death, and wild-type mice can be made resistant through the administration of tPA inhibitors. Similar resistance is observed in mice deficient for tPA’s substrate, plasminogen. tPA may function under physiological conditions to regulate neurite outgrowth. In addition, tPA via a non-proteolytic mechanism has a second role, which is to trigger the activation of microglial cells. Microglia are immune-competent, macrophage-like cells that reside in the CNS and are involved in neurodegeneration under conditions of excessive stimulation, or are hypothesized to affect neuronal structural changes occurring in response to neuronal activity. Our research interests concern the communication, signaling events and cell-cell interactions between neurons and microglia subsequent to normal or exaggerated stimulation of the central nervous system that lead to reorganization of neuronal connections in the brain or neuronal cell death.
Mirrione MM, Schiffer W, Fowler J, Alexoff D, Dewey SL and Tsirka SE. (2007) A novel approach for imaging brain-behavior relationships in mice reveals unexpected metabolic patterns during seizures in the absence of tissue plasminogen activator , NeuroImage, in press.
Bhasin M, Wu M, Tsirka SE. (2007) Modulation of microglial/macrophage activation by macrophage inhibitory factor (TKP) or tuftsin (TKPR) attenuates the disease course of experimental autoimmune encephalomyelitis, BMC Immunology, 8: 10 [Epub ahead of print].
Thiex R, Tsirka SE. (2007) Brain edema after intracerebral hemorrhage: mechanisms, treatment options, management strategies, and operative indications. Neurosurg Focus. 22:E6. PMID: [PubMed - in process].
Parathath SR, Gravanis I, and Tsirka, SE (2007) Nitric oxide synthase isoforms undertake unique roles during excitotoxicity, Stroke 38:.
Sheehan JJ, Zhou C, Gravanis I, Rogove AD, Wu Y-P, Bogenhagen DF, Tsirka SE (2007) Proteolytic activation of monocyte chemoattractant protein 1 by plasmin underlies excitotoxic neurodegeneration in mice, J Neurosci 27:.
Mirrione MM, Schiffer WK, Siddiq M, Dewey SL, Tsirka SE (2006). PET imaging of glucose metabolism in a mouse model of temporal lobe epilepsy. Synapse 59 119-21.
Parathath SR, Parathath S, Tsirka SE (2006). Nitric oxide mediates neurodegeneration and breakdown of the blood-brain barrier in tPA-dependent excitotoxic injury in mice. J Cell Sci. 119 339-49.
Gravanis I, Tsirka SE (2005). Tissue plasminogen activator and glial function. GLIA 49 177-83.
Wang J, Tsirka SE (2005). Tuftsin fragment 1-3 is beneficial when delivered after the induction of intracerebral hemorrhage. 36 613-8.
Zhang Y, Kanaho Y, Frohman MA, Tsirka SE (2005). Phospholipase D1-promoted release of tissue plasminogen activator facilitates neurite outgrowth. J Neurosci. 25.
Wang J, Tsirka SE (2005). Neuroprotection by inhibition of matrix metalloproteinases in a mouse model of intracerebral haemorrhage. 128.
Zhang Y, Pothakos K, Tsirka SA (2005). Extracellular proteases: biological and behavioral roles in the mammalian central nervous system. 66 161-88.
Sheehan JJ, Tsirka SE (2005). Fibrin-modifying serine proteases thrombin, tPA, and plasmin in ischemic stroke: a review. GLIA 50 340-50.
Xanthopoulos K, Paspaltsis I, Apostolidou V, Petrakis S, Siao CJ, Kalpatsanidis A, Grigoriadis N, Tsaftaris A, Tsirka SE, Sklaviadis T (2005). Tissue plasminogen activator in brain tissues infected with transmissible spongiform encephalopathies. 20 519-27.
Wang J, Tsirka SE (2005). Contribution of extracellular proteolysis and microglia to intracerebral hemorrhage. 3 77-85.
Zhang Y, Huang P, Du G, Kanaho Y, Frohman MA, Tsirka SE (2004). Increased expression of two phospholipase D isoforms during experimentally induced hippocampal mossy fiber outgrowth. GLIA 46 74-83.
Siddiq MM, Tsirka SE (2004). Modulation of zinc toxicity by tissue plasminogen activator. 25 162-71.
Thiex R, Mayfrank L, Rohde V, Gilsbach JM, Tsirka SA (2004). The role of endogenous versus exogenous tPA on edema formation in murine ICH. 189 25-32.
Wang J, Rogove AD, Tsirka AE, Tsirka SE (2003). Protective role of tuftsin fragment 1-3 in an animal model of intracerebral hemorrhage. 54 655-64.
Siao CJ, Fernandez SR, Tsirka SE (2003). Cell type-specific roles for tissue plasminogen activator released by neurons or microglia after excitotoxic injury. J Neurosci. 23.
Indyk JA, Chen ZL, Tsirka SE, Strickland S (2003). Laminin chain expression suggests that laminin-10 is a major isoform in the mouse hippocampus and is degraded by the tissue plasminogen activator/plasmin protease cascade during excitotoxic injury. 116 359-71.
Lu W, Bhasin M, Tsirka SE (2002). Involvement of tissue plasminogen activator in onset and effector phases of experimental allergic encephalomyelitis. J Neurosci. 22 10781-9.
Rogove AD, Lu W, Tsirka SE (2002). Microglial activation and recruitment, but not proliferation, suffice to mediate neurodegeneration. Cell Death Differ. 9 801-6.
Tsirka SE (2002). Tissue plasminogen activator as a modulator of neuronal survival and function. 30 222-5.
Siao CJ, Tsirka SE (2002). Extracellular proteases and neuronal cell death. 48 151-61.
Siao CJ, Tsirka SE (2002). Tissue plasminogen activator mediates microglial activation via its finger domain through annexin II. J Neurosci. 22 3352-8.
Lu W, Tsirka SE (2002). Partial rescue of neural apoptosis in the Lurcher mutant mouse through elimination of tissue plasminogen activator. 129.
Mori T, Wang X, Kline AE, Siao CJ, Dixon CE, Tsirka SE, Lo EH (2001). Reduced cortical injury and edema in tissue plasminogen activator knockout mice after brain trauma. 12.
Wu YP, Siao CJ, Lu W, Sung TC, Frohman MA, Milev P, Bugge TH, Degen JL, Levine JM, Margolis RU, Tsirka SE (2000). The tissue plasminogen activator (tPA)/plasmin extracellular proteolytic system regulates seizure-induced hippocampal mossy fiber outgrowth through a proteoglycan substrate. J Cell Biol. 148.
Rogove AD, Siao C, Keyt B, Strickland S, Tsirka SE (1999). Activation of microglia reveals a non-proteolytic cytokine function for tissue plasminogen activator in the central nervous system. J Cell Sci. 112 ( P.
Rogove AD, Tsirka SE (1998). Neurotoxic responses by microglia elicited by excitotoxic injury in the mouse hippocampus. Current Biology 8 19-25.
Wang YF, Tsirka SE, Strickland S, Stieg PE, Soriano SG, Lipton SA (1998). Tissue plasminogen activator (tPA) increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice. 4 228-31.
Mecenas PE, Tsirka SE, Sall�s F, Strickland S (1997). Removal of tissue plasminogen activator does not protect against neuronal degeneration in the cerebellum of the weaver mouse. 772 233-8.
Colley WC, Altshuller YM, Sue-Ling CK, Copeland NG, Gilbert DJ, Jenkins NA, Branch KD, Tsirka SE, Bollag RJ, Bollag WB, Frohman MA (1997). Cloning and expression analysis of murine phospholipase D1. Biochem J. 326 ( P 745-53.
Tsirka SE, Bugge TH, Degen JL, Strickland S (1997). Neuronal death in the central nervous system demonstrates a non-fibrin substrate for plasmin. Proc Natl Acad Sci U S A. 94.
Tsirka SE (1997). Clinical implications of the involvement of tPA in neuronal cell death. Journal of molecular medicine 75 341-7.
Tsirka SE, Rogove AD, Bugge TH, Degen JL, Strickland S (1997). An extracellular proteolytic cascade promotes neuronal degeneration in the mouse hippocampus. 17 543-52.
Tsirka SE, Rogove AD, Strickland S (1996). Neuronal cell death and tPA. Nature 384 123-4.
West MF, Verrotti AC, Sall�s FJ, Tsirka SE, Strickland S (1996). Isolation and characterization of two novel, cytoplasmically polyadenylated, oocyte-specific, mouse maternal RNAs. Dev Biol. 175 132-41.
Gualandris A, Jones TE, Strickland S, Tsirka SE (1996). Membrane depolarization induces calcium-dependent secretion of tissue plasminogen activator. 16 2220-5.
Strickland S, Gualandris A, Rogove AD, Tsirka SE (1996). Extracellular proteases in neuronal function and degeneration. 61 739-45.
Tsirka SE, Gualandris A, Amaral DG, Strickland S (1995). Excitotoxin-induced neuronal degeneration and seizure are mediated by tissue plasminogen activator. Nature 377 340-4.
Carroll PM, Tsirka SE, Richards WG, Frohman MA, Strickland S (1994). The mouse tissue plasminogen activator gene 5' flanking region directs appropriate expression in development and a seizure-enhanced response in the CNS. 120.
Tsirka SE, Turck CW, Coffino P (1993). Multiple active conformers of mouse ornithine decarboxylase. Biochem J. 293 ( P 289-95.