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The focus of my research is the blood brain barrier (BBB)/Neurovasular Unit in health and disease and specifically the effects of inflammatory pain and stroke on the BBB. The BBB plays a vital role in maintaining brain homeostasis. Composition of the brain interstitial fluid is controlled within a precise range, independent of fluctuations within the blood, allowing optimal neuronal function to occur. The BBB is situated at the endothelial tight junctions of the cerebral microvessels.
Fig.1. Schematic showing the BBB/Neurovascular unit. Note the loose association of astrocytes to endothelial cells.
The cerebral endothelial cells form a continuous membrane with no fenestrations, unlike peripheral vessels. The endothelial cells of the BBB are connected via a network of tight junctions that create a rate-limiting barrier to paracellular diffusion of solutes. Structurally, tight junctions form a continuous network of parallel, interconnected, intramembrane protein strands, which are composed of an intricate combination of transmembrane and cytoplasmic proteins linked with the actin-based cytoskeleton, allowing the tight junction to form a seal while remaining capable of rapid modulation and regulation
Fig.2. Schematic of the tight junctions of the BBB. Tight junctions consist of three main groups of proteins. They are transmembrane proteins (Claudins, occuludin and junctional adhesion molecule), accessory proteins (ZO-1 /2 /3 etc) and cytoskeletal proteins (actin etc). All three groups interact to maintain the tight junctions (for a more detailed review see Hawkins and Davis, 2005). These proteins can be modulated via a number of mechanisms. In neuroinflammatory disorders (Alzheimers, Parkinsons and multiple sclerosis), alterations in these proteins contribute to disease progression.
Lochhead, J.J., G. McCaffrey, C. Quigley, J. Finch, K. DeMarco and T.P. Davis. Tempol reverses the ROS induced disruptions in BBB integrity during hypoxia-reoxygenation. J. Cerebral Blood Flow and Metabolism. In Press. 2010
Willis, C.L., D. S. Meske, and T.P. Davis. Protein kinase C activation modulates reversible increase in cortical blood-brain barrier permeability and tight junction protein expression during hypoxia and post-hypoxic reoxygenation . J. Cerebral Blood Flow and Metabolism. In press, 2010.
Ronaldson, P.T., J. D. Finch, K.M. DeMarco, C.M. Solinsky, C. E. Quigley and T.P. Davis. Increased functional expression of organic anion transporting polypeptide 1a4 at the blood-brain barrier during peripheral inflammatory pain. J Pharmacology experimental Therapeutics. In Press. 2010.
Lochhead, J. J., G. McCaffrey, C. E. Quigley, J. Finch, K. DeMarco and T.P. Davis. Oxidative stress increases blood-brain barrier permeability and induces alterations in occludin during hypoxia-reoxygenation. J. Cerebral Blood Flow and Metabolism. In press. 2010.
McCaffrey, G.W., C Willis, W. Staatz, N. Nametz, C. Quigley, S. Hom, J. Lochhead and T.P. Davis. Occludin oligomeric assemblies at tight junctions of the blood brain barrier dynamically respond to hypoxia and reoxygenation stress. J. Neurochemistry 110,1:58-71.2009.
Wang, Y., M. Thiyagarajan, N. Chow, I. Singh, H. Guo, T.P. Davis and B. Zlokovic. Differential Neuroprotection and Risk for Bleeding from Activated Protein C with varying degree of Anticoagulant Activity. Stroke 40,5. 1864-1869. 2009.
Ronaldson, P.T., K.M. DeMarco, L. Sanchez-Covarubias, C.M. Solinsky and T.P. Davis. Transforming growth factor Beta signaling alters permeability and tight junction protein expression at the blood brain barrier during inflammatory pain. J. Cerebral Blood Flow and Metabolism 29,6. 1084-1098.2009.
Willis, C.L. and T.P. Davis. Chronic inflammatory pain and the neurovascular unit: a central role for maintaining BBB integrity? Current Pharmaceutical Design 14(16): 1625-1643, 2008
McCaffrey, G.W., M.J. Seelbach, W.D. Staatz, N Nametz, C. Quigley, C.R. Campos, T.A. Brooks
and T.P. Davis. Occludin oligomeric assembly at tight junctions of the blood-brain barrier is
disrupted by peripheral inflammatory hyperalgesia. J. Neurochemistry. 106(6):2395-2409. 2008.
Brooks, T.A., N. Nametz, R. Charles and T.P. Davis. Diclofenac attenuates the regional effect of
lambda carrageenan on BBB function and cytoarchitecture. J.Pharmacol Exp.Ther. 325(2): 665-673. 2008.
Neuwelt, E., N. Joan Abbott, L.Abrey, W. A. Banks, B. Blakley, T.P. Davis, B. Engelhardt, P.
Grammas, M. Nedergard, J. Nutt, W. Pardridge, G. Rosenberg, Q. Smith and L. Drewes.
Strategies to advance translational research into brain barriers. Lancet Neurology 7(1): 84-96, 2008.
Campos, C.R., S, Hom, R.D. Egleton and T.P. Davis. Nociceptive inhibition prevents inflammatory pain induced changes in the blood brain barrier. Brain Research 1221: 6-13. 2008.
Witt, K.A., K.S. Mark , K. Sandoval and T.P. Davis. Reoxygenation stress on Blood Brain Barrier Paracellular Permeability and Edema in the Rat. Microvascular Research 75(1):91-96. 2008
McCaffrey, G., W. Staatz, R. Egleton, M. Seelbach, C. Campos and T.P. Davis. Tight Junctions contain Oligomeric protein assembly critical for maintaining blood brain barrier integrity in vivo. J. Neurochemistry 103:2540-2555. 2007
Hom, S., M.A. Fleegal, R.D. Egleton, C.R. Campos, B. Hawkins and T.P. Davis. Comparative changes is the blood brain barrier and cerebral infarction of SHR and WKY rats. American Journal of Physiology (Regulatory, Integrative and Comparative Physiology) 292 (5).1881-1892. 2007
Seelbach, M.J., J.D. Huber, T. Brooks, R.D. Egleton, K.A. Witt and T.P. Davis. Effect of lambda carrageenan-induced inflammatory pain on brain uptake of morphine and the potential role of P-glycoprotein. J. Neurochemistry . 102,5.1677-1690. 2007
Huber, J.D., C.R. Campos, K.S. Mark and T.P. Davis. Alterations in blood-brain barrier ICAM-1 expression and microglial activation following lambda carrageenan induced inflammatory pain. American Journal of Physiology (Heart and Circulatory) 290(2):H732-740. 2006
Witt, K.A. and T.P. Davis. CNS Drug Delivery: Opioid Peptides and the Blood Brain Barrier. The AAPS Journal 7 (4) 9. 2006
Brooks, T.A., C.R. Campos, R.D. Egleton, M. Seelbach, N. Nametz and T.P. Davis. Biphasic cytoarchitecture and functional changes in the BBB induced by chronic inflammatory pain. Brain Research 1120(1).172-182. 2006
Fleegal, M.A., S. Hom, L.K. Borg and T.P. Davis. Hypoxia and post-hypoxic reoxygenation modulate PKC activity and protein expression in endothelial cells of the blood-brain barrier. American J. Physiology (Heart and Circulatory) 289(5):H2012-2019.2005
Hawkins, B. T. and T.P. Davis. The blood-brain barrier/neurovascular unit in health and disease. Pharmacological Reviews 57(2):173-185, 2005
Brooks, T.A., B.T. Hawkins, J.D. Huber, R.D. Egleton and T.P. Davis. Chronic inflammatory pain leads to increased blood-brain barrier permeability and tight
junction protein alterations. American J. Physiology (Heart and Circulatory) 289(2):H738-H743. 2005
Witt, K.A., K.S. Mark, J.D. Huber and T.P. Davis. Hypoxia Inducible Factor and Nuclear Factor Kappa-B Activation in Blood Brain Barrier Endothelium under Hypoxic/Reoxygenation Stress. J. Neurochemistry 92(1):203-214, 2005
Egleton, R.D. and T.P. Davis. Development of Neuropeptide Drugs that Cross the Blood- Brain Barrier. NeuroRx. Jan; 2(1), 44-53. 2005
Brown, R.C. and T.P. Davis. Hypoxia/Aglycemia alters expression of occludin and actin in brain endothelial cells. Biochemical and Biophysical Research Communications 327(4):1114-1123, 2005
Hawkins, B.T., R.D. Egleton and T.P. Davis. Modulation of cerebral microvascular permeability by endothelial nicotinic acetylcholine receptors. American J. Physiology (Heart and Circulatory) 289(1): H212-H219. 2005