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

THE JANIGROLABORATORYPROJECT SCIENTISTSBenedict Albensi, Ph.D.Lily Krizanac-Bengez, M.D., Ph.D.Thomas Masaryk, M.D.Shobu Namura, M.D., Ph.D.Fiona Parkinson, Ph.D.Peter Rasmussen, M.D.RESEARCH ASSOCIATELuca Cucullo, Ph.D.RESEARCH FELLOWSTamer A. Mohammed Attia, M.D.Gabrielle Dini, Ph.D.Andrew Kanner, M.D.Nicola Marchi, Ph.D.Gabriel Moddel, M.D., Ph.D.Emil Zeynalov, M.D.TechnologistsVincent Fazio, M.S.Kerri Hallene, B.S.Mohammed Hossain, M.S.Kelly Kight, B.S.Joseph Waterman, B.S.CLINICAL FELLOWEdwin Cunningham, M.D.COLLABORATORSN. Joan Abbott, Ph.D. 1Gene Barnett, M.D. 2Giorgio Battaglia, M.D. 3William Bingaman, M.D. 2Marco De Curtis, M.D. 3Anthony Furlan, M.D. 4Gerry Grant, M.D., Ph.D. 5Imad Najm, M.D., Ph.D. 4Erik Pioro, M.D., Ph.D. 4Peter Rasmussen, M.D. 2P.A. Schwartzkroin, Ph.D. 5Annamaria Vezzani, Ph.D. 3Michael Vogelbaum, M.D.,Ph.D. 21King’s College, London, UK2Dept. of Neurol. Surg., CCF3Univ. of Milan, Italy4Dept. of Neurology, CCF5Univ. of Washington, SeattleBlood-Brain Barrier in Health and Disease:Clinical ImplicationsWork in Dr. Janigro’s laboratory focusesprimarily on the investigation of glialendothelialinteractions in the ontogenesisand failure of the blood-brain barrier. To thisend, he developed a three-dimensional model ofthe blood-brain barrier in vitro that has become afundamental tool used to study how endothelialcells grown under physiological conditions reactto intra- and extraluminal signals. The research hasexpanded from the initial pharmacological andphysiological examination of the development ofthe blood-brain barrier to molecular analysis ofgene expression changes that characterizeendothelial-glial differentiationduring vasculogenesis. Thepossibility that some forms ofneurological disorders arise fromdevelopmental failure of thesemechanisms is also being investigatedusing transgenic animals withevident neuronal migrationdisorders. A novel non-invasiveperipheral blood test has beendeveloped to assess integrity of theblood-brain barrier. This test isbased on the extravasation of acerebrospinal fluid protein inperipheral blood when the bloodbrainbarrier becomes leaky. Thisdiagnostic procedure is now beingevaluated as a predictor of brain tumor recurrence,brain metastasis, and propensity to chronicneurological disease, as well as for intraoperativeassessment of neurologic deterioration.Peripheral markers of brain damageS100β is a protein that is constitutivelyexpressed by brain astrocytes and physiologicallydoes not appear in minimal concentration in thesystemic circulation. Recent evidence from thislaboratory demonstrates that S100β is a sensitivemarker of blood-brain barrier failure that doesDamir Janigro, Ph.D.not necessarily indicate brain damage.With this in mind, Dr. Janigro and hiscollaborators, Nicola Marchi, Ph.D., and AndrewKaner, M.D., prospectively studied serum S100βlevels in patients undergoing hypersomatic bloodbrainbarrier (BBB) disruption for intra-arterialchemotherapy for primary central nervous systemlymphoma. These studies indicated that S100?directly correlated with the degree of clinical andradiological signs of BBB disruption in patientswho were enrolled in the hyperosmotic study.Furthermore, in patients with neoplastic brainlesions, Gadolinium enhancement on MRIcorrelated with elevated S100βlevels versus non-enhancing scans.Primary brain tumors orCNS metastases presented withsignificantly elevated serum S100β.The same researchers havealso identified a protein markerthat could detect disease anddetermine when the body may bereceptive to medication. Thisprotein marker, dubbedtranstyretin monomer (TTR),could deliver potentially lifesavingmedications when thebody’s natural defense mechanismsare temporarily breached.The defense mechanisms to whichDr. Janigro refers protect the brain from foreignsubstances by creating barriers between the bloodand the brain, as well as between the blood andcerebrospinal fluid (CSF). This finding may havesignificant implications in the development ofsimple diagnostic tools for conditions affectingthe central nervous system. Additionally,discovery of this marker may help us manage ordiagnose disorders such as stroke, brain tumors,inflammations of the nervous system and othercerebrovascular disorders.Marroni, M., Agaral, M., Kight, K., Hallene, K.L., Hossain, M., Cucullo, L., Signorelli, K., Namura, S,and D. Janigro (2003) Relationship between expression of multiple drug resistance proteins and p53 tumorsuppressor gene proteins in human brain astrocytes. Neuroscience 2003 in press.Kanner, A.A., Marchi, N., Fazio, V., Mayberg, M.R., Koltz, M.T., Siomin, V., Stevens, G.H., Masaryk, T.,Ayumar, B., Vogelbaum, M.A., Barnett, G.H., and D. Janigro (2003) Serum S100beta: a noninvasivemarker of blood-brain barrier function and brain lesions. Cancer 97:2806-13.Cucullo, L., Marchi, N., Marroni, M., Fazio, V., Namura, S., and D. Janigro (2003) Blood-brain barrierdamage induces release of alpha 2-macroglobulin. Mol Cell Proteomics 2003.Marroni, M., Marchi, N., Cucullo, L., Abbott, N.J., Signorelli, K., and D. Janigro (2003) Vascular and parenchymalmechanisms in multiple drug resistance: a lesson from human epilepsy. Curr Drug Targets4:297-304.Marchi, N., Fazio, V., Cucullo, L., Kight, K., Masaryk, T., Barnett, G., Vogelbaum, M., Kinter, M., Rasmussen,P., Mayberg, M.R., and D. Janigro (2003) Serum transthyretin monomer as a possible markerof blood-to-CSF barrier disruption. J Neurosci 23:1949-55.158