Colin L Willis, Ph.D.
Assistant Professor of Pharmacology
Location
Credentials
Education
Clinical Affiliations
Research
Current research
The blood-brain barrier (BBB) is a highly regulated interface that separates the peripheral circulating blood supply and the central nervous system (CNS). Brain capillary endothelial cells form the structural basis of the BBB restricting the passage of blood borne proteins, many neurotoxic agents and hydrophilic molecules, while allowing diffusion of small hydrophobic molecules (O2 and CO2) and selective transcellular transport of nutrients and other essential components into the brain parenchyma. However, in many neurodegenerative diseases including stroke, multiple sclerosis, rheumatoid arthritis and AIDS dementia, there is a loss of BBB integrity.
My research interests focus on changes at the neurovascular unit, specifically looking at glia/endothelial interactions, CNS inflammation and intracellular mechanisms which modify BBB integrity. For these studies I am using two in vivo models, 1) chemically-induced astrocyte lesion provides a non-invasive model to study reversible BBB dysfunction, 2) a model of global cerebral hypoxia, to demonstrate a size selective changes in blood-brain barrier integrity in various neuroanatomical brain regions. Recent studies have shown that during hypoxic conditions, there is activation of specific protein kinase C isozymes and raised levels of pro-inflammatory cytokines. This results in modification of tight junction protein expression (occludin, claudin-5 and ZO-1) on the vascular endothelial cells. These studies have identified several potential sites of pharmacological intervention which I am testing to determine whether BBB integrity changes can be attenuated during and following hypoxic stress. By identification of novel targets of therapy this research has important translational implications for drug development and delivery and therapy of stroke and cerebral ischemia.
Selected publications
Willis CL. Glia-induced reversible disruption of blood-brain barrier integrity and neuropathological response of the neurovascular unit. Toxicologic Pathology (submitted) 2010.
Willis CL, Meske DS, Davis TP. Protein kinase-C activation modulates reversible increase in cortical blood-brain barrier permeability and tight junction protein expression during hypoxia and post-hypoxic reoxygenation. JCBFM (in press) 2010.
McCaffrey G, Willis CL, Staatz WD, Nametz N, Quigley C, Hom S, Lochhead J, Davis TP. Occludin oligomeric assemblies at tight junctions of the blood-brain barrier dynamically respond to hypoxia and reoxygenation with changes in structural integrity and isoform composition. J Neurochem 110(1) 58-71 2009.
Willis CL, Davis TP. Chronic inflammatory pain and the neurovascular unit: A central role for glia in maintaining BBB integrity. Current Pharmaceutical Design 14 (2008) 1625-1643. (selected for cover)
Willis CL, Garwood CJ, Ray DE. A size selective vascular barrier in the rat area postrema formed by perivascular macrophages and the extracellular matrix. Neurosci 150 (2007) 498-509
Willis CL, Taylor GL, Ray DE. Microvascular P-glycoprotein expression at the blood-brain barrier following focal astrocyte loss and at the fenestrated vasculature of the area postrema. Brain Res 1173 (2007) 126-136.
Willis CL, Ray DE. Antioxidants attenuate MK-801-induced cortical neurotoxicity in the rat. Neurotox 28 (2007) 161-167.
Willis CL, Ray DE, Marshall, Elliot G, Evans JG, Kind CN. Basal forebrain cholinergic lesions reduce heat shock protein72 response but not pathology induced by the NMDA antagonist MK-801 in the rat cingulate cortex. Neurosci Letts 407 (2006) 112-117.
Willis CL, Leach L, Clarke GJ, Nolan CC, Ray DE. Reversible disruption of tight junction complexes in the rat blood-brain barrier, following transitory focal astrocyte loss. Glia 48 (2004) 1-13. (selected for cover)
Willis CL, Nolan CC, Reith SN, Lister T, Guerin CJ, Mavroudis G, Prior MJW, Ray DE. Focal astrocyte loss is followed by microvascular damage, with subsequent repair of the blood-brain barrier in the apparent absence of direct astrocytic contact. Glia 45 (2004) 325-337.
Research interests
a) cell/cell interactions at the neurovascular unit. In particular the role of astrocytes in modulating the integrity of the blood-brain barrier;
b) intracellular signaling mechanisms which regulate tight and adherens junctional proteins resulting in modulation of blood-brain barrier integrity.