Scientific Report 2003-2004 - Cleveland Clinic Lerner Research ...

CENTER FORCEREBROVASCULASRESEARCHCenter forCerebrovascular ResearchDIRECTORDamir Janigro, Ph.D.INVESTIGATORSBenedict Albensi, Ph.D. 1Gene Barnett, M.D. 1Nicholas Boulis, M.D. 1Lily Krizanac-Bengez, M.D., Ph.D. 1Luca Cucullo, Ph.D. 1Shailesh Desai, Ph.D. 1Miranda Kapural, M.D. 1Matteo Marroni, Ph.D. 1Marc Mayberg, M.D. 1Imad Najm, M.D. 1Shobu Namura, M.D., Ph.D. 1Fiona Parkinson, Ph.D. 2Peter Rasmussen, M.D. 1Mike Vogelbaum, M.D., Ph.D. 31Dept. of Neurological Surgery,CCF2Univ. of Manitoba, Winnipeg,MB, Canada3Dept. of Cancer Biology, CCFFELLOWSEmil Zeynalov, M.D.Tamer A. Mohammed Attia, M.D.TECHNICIANJoseph Waterman, B.S.COLLABORATORSJoan Abbott, Ph.D. 1Marco DeCurtis, M.D. 2Paul DiCorleto, Ph.D. 3Howard Fine, M.D. 4Gerry Grant, M.D., Ph.D. 5Claudia Martini, Ph.D. 6Jay Nelson, Ph.D. 7P.A. Schwartzkroin, Ph.D. 8Dana Stanimirovic, M.D., Ph.D. 91King’s College, CambridgeUniv., London, UK2Univ. of Milano, Italy3Dept. of Cell Biology, CCF4National Cancer Institute, NIH,Bethesda, MD5Univ. of Washington, Seattle6Univ. of Pisa, Italy7Oregon Health Sciences Univ.,Portland8Univ. of California/Davis, CA9National Research Council,Ottawa, Ont., Canada156The Center for Cerebrovascular Researchwas created in 1998 as part of the bridgeprogram between the Departments ofNeurosurgery and Neurology and the LernerResearch Institute. The main goal of this effortwas to promote cerebrovascular research, anoften neglected but clinically relevant field of theneurosciences. The Center provides state-of-theartfacilities to interactively perform a broadvariety of experiments, ranging from animalmodels of acute neurological disorders tomolecular and electrophysiological investigationof the mechanisms of human disease. The Centerenjoys a vast array of local and extramuralcollaborations, and members of the Center havebeen actively involved in efforts aimed atpromoting awareness of the importance ofcerebrovascular research to treat and preventneurological diseases. The pre-clinical (“translational”)relevance of the Center for CerebrovascularResearch is emphasized by the almost equaldistribution of M.D. and Ph.D. staff among itsinvestigators.Although the understanding of hownonneuronal mechanisms participate in theoverall complexity of neuronal function andneuropathogenesis constitutes the main focus ofthe Center, individual investigators are approachingthis task from different perspectives. Themajor ongoing efforts include the following.The Effect of Shear Stress on the Blood-Brain BarrierCurrent research investigation focusesprimarily on glia-endothelial interactions at theblood-brain barrier during ischemia, using adynamic in vitro model of blood-brain barrier(DIV-BBB). The goal is to investigate therespective roles of ischemic components - shearstress with/without hypoxia and/or hypoglycemiain the modulation of the inflammatory responseof the vessel wall, and subsequent alterations inthe blood-brain barrier. There is substantialevidence linking BBB disruption to inflammatoryprocesses involving cytokines, chemokines andleukocyte-endothelial cell interactions. Thefollowing aims have been studied:• NO-modulated cytokine production byastrocytes or WBC-dependent cytokinerelease by WBC, endothelium and astrocytesas critical precedents to subsequentinflammation.• Expression of cell adhesion molecules duringflow cessation/reperfusion correlated toleukocyte adhesion and subsequent BBBdisruption.• The nature of WBC-endothelial celladhesion examined in terms of cytokinestimulatedprostaglandin synthesis andrelease of reactive oxygen species.• The role of matrix metalloproteinases(MMP-2, -3 and -9) in inflammationmediatedBBB disruption.This research project should provide abetter understanding of the relationship betweenmicrovascular blood flow reductions and BBB,and may lead to effective therapies to preventBBB disruption after stroke.Synaptic Organization and PhysiologyRsearch LabFocus Area: The exploration of cellularand molecular mechanisms associated with normalvs. pathologic synaptic transmission and plasticityin the hippocampus and cortex. The hippocampalformation is a critical brain region for memoryconsolidation that is highly sensitive to acuteinjury. Of particular interest is how acute formsof brain injury, such as ischemia, disrupt processesbelieved to be associated with synaptic plasticityand cellular memory encoding and also, how acuteinjury may lead to long-term changes, such aswith Alzheimer’s dementia and/or epilepticseizures. Past and present investigations include:• Temporal evolution of hypoxia-ischemia andtrauma in the neonatal vs. adult hippocampus.• Mitochondrial dysfunction in stroke/trauma,and hippocampal synaptic plasticity.• Tumor necrosis factor and hippocampalsynaptic plasticity.• Natural products, NMDA/AMPA-receptormediated transmission, and hippocampalsynaptic plasticity.• Suppression of epileptiform activity byprolonged electrical stimulation in thehippocampus.• Gene-transfer based neuromodulation ofGABA-mediated inhibition in the hippocampusIn vitro electrophysiological techniques(extracellular, intracellular, multielectrode array,and patch clamp recordings) have been performedin human and animal cells, brain slices, andorganotypic cultures for studies involving braininjury and long-term potentiation/depression(LTP/LTD), a molecular model of learning/memory. Other research has employed functionaland conventional in vivo MRI techniques, whichallows an important comparison with the abovein vitro techniques. Furthermore, investigationshave attempted to identify therapeutic targets inCNS diseases and pathology that may havepotential for drug development.This research bridges clinical expertise withlaboratory investigation for studying basicpathophysiological mechanisms underlying stroke,trauma, epilepsy, and dementia.Dynamic in vitro Model of BBBFocus Area: Studies performed on viable invitro models are set to accelerate the design ofdrugs that selectively and aggressively can targetthe CNS. Several systems in vitro attempt toContinued on Page 161