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pburger@jhmi.edu |
| Phone |
(410) 955-8378 |
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Peter C. Burger, M.D.
Primary Appointment in Pathology; Secondary Appointments in Neurosurgery, Oncology
My principal interest is in surgical neuropathology of both neoplastic and non-neoplastic diseases. For both, I am seeking the best methods by which these lesions can be diagnosed, and their biological behavior projected. Our current work explores molecular basis of gliomas, specifically molecular or cytogenetic abnormalities that correlate with tumor type and prognosis. We are involved in a multi-institutional study of the pathological cytogenetic, and molecular features of gliomas, particularly those that can be used to distinguish oligodendrogliomas from histologically similar lesions such as astrocytoma. We are also categorizing the cytogenetic and molecular features of pediatric astrocytomas and to subdivide medulloblastomas on the basis of their cytogenetic and molecular anatomy. With joint appointments in Oncology and Neurosurgery, I work closely with these disciplines in the evaluation of new therapies for CNS tumors. We have an active consult service for the interpretation of surgical specimens for brain and spinal cord tumors and other lesions.
Publications
Burger, P.C., Minn, A.Y., Smith, J.S., Borell, T.J., Jedlicka, A.E., Huntley,B.K., Goldthwaite, P.T., Jenkins, R.B., and Feuerstein, B.G.: Losses of Chromosomal Arms 1p and 19q in the Diagnosis of Oligodendroglioma. A Study of Paraffin-Embedded Sections. Modern Pathology 14:842-853, 2001.
Burger, P.C., Pearl, D.K., Aldape, K., Yates, A.J., Scheithauer, B.W.,Passe, S.M., Jenkins, R.B., and James, C.D. Small Cell Architecture - Ahistological Equivalent of EGFR Amplification in Glioblastoma Multiforme? J.Neuropathol. Exp. Neurol. 60:1099-1104, 2001.
Eberhart, C.G., Kratz, J.E., Schuster, A., Goldthwaite, P., Cohen, K.J.,Perlman, E.J., and Burger, P.C.: Comparative Genomic Hybridization Detects an Increased Number of Chromosomal Alterations in Large Cell/Anaplastic Medulloblastomas. Brain Pathology 121:36-44, 2001.
Eberhart, C.G., Kepner, J.L., Goldthwaite, P.T., Kun, L.E., Duffner, P.K.,Friedman, H.S., Strother, D.R., and Burger, P.C.: Histopathologic Grading of Medulloblastomas: A Pediatric Oncology Group Study. Cancer 94:552-560,2002. |
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ceberha@jhmi.edu |
| Phone |
(410) 502-5185 |
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Charles G. Eberhart, M.D., Ph.D.
Primary Appointment in Pathology
Member, Graduate Program in Pathobiology
My laboratory studies the pathology and molecular biology of pediatric brain tumors. I am particularly interested in how the signaling pathways involved in normal CNS development become aberrantly activated in brain tumors. We study these issues using human tumor specimens, tumor cell lines, and transgenic mouse tumor models. Current projects include: (1) developing new models of large cell/anaplastic medulloblastomas based on c-Myc overexpression; (2) identification and functional analysis of c-Myc targets in brain tumors in vitro and in vivo; (3) analysis of Notch signaling in pediatric brain tumors; and (4) analysis of Hedgehog signaling in brain tumors.
Publications
X Fan, I Mikolaenko, I Elhassan, XZ Ni, Y Wang, D Ball, DJ Brat, A Perry, and CG. Eberhart. Notch1 and Notch2 have opposite effects on embryonal brain tumor growth. Cancer Res. 2004, 64:7787-93
CG Eberhart, J Kratz, Y Wang, K Summers, D Stearns, K Cohen, CV Dang. and PC Burger. Histopathological and Molecular Prognostic Markers in Medulloblastoma: c-myc, N-myc, TrkC and Anaplasia. J Neuropath. Exp. Neurol 2004, 63(5):441-9
Fan X, Wang Y, Kratz J, Brat DJ, Robitaille Y, Moghrabi A, Perlman EJ, Dang CV, Burger PC, Eberhart CG. hTert Gene Amplification and Increased mRNA Expression in CNS Embryonal Tumors, Am J Pathol 2003, 162(6):1763-9.
Eberhart CG, Kepner JL, Goldthwaite PT, Kun LE, Duffner PK, Friedman HS, Strother DR, Burger PC. Histopathologic grading of medulloblastomas: a pediatric oncology group study. Cancer 2002, 94:552-560.
Eberhart CG, Kratz JE, Schuster A, Goldthwaite P, Cohen KJ, Perlman EJ, and Burger PC. Comparative Genomic Hybridization Detects An Increased Number of Chromosomal Alterations in Large Cell/Anaplastic Medulloblastomas. Brain Pathology 2002, 12:36-44 |
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Walter E. Kaufmann, M.D.
Primary Appointment in Pathology; Secondary Appointments in Neurology, Pediatrics, Psychiatry, and Radiology
My investigations deal with the neurobiologic basis of mental retardation of genetic oFrigin, specifically Down, Rett, and Fragile X syndromes. Our multidisciplinary approach covers the genotype to neurobehavioral phenotype spectrum, including studies of gene expression and signaling pathways, molecular and anatomical characterization of neuronal differentiation, morphometric analyses by quantitative MRI, and delineation of cognitive and behavioral features of each condition. This multi-level research program intends to readily bring advances in molecular biology, developmental neurobiology, neuroimaging, and behavioral sciences to the study of these developmental disorders, as well as attempts to identify markers and methods that can be applied as diagnostic and therapeutic tools.
Publications
Aber KM, Nori P, MacDonald S, Bibat G, Jarrar MH, Kaufmann WE (2003) Methyl-CpG-binding protein 2 is localized in the postsynaptic compartment: an immunochemical study of subcellular fractions. Neuroscience 116: 77-80.
Kaufmann WE, Cooper KL, Mostofsky SH, Capone GT, Kates WR, Newschaffer CJ, Bukelis I, Stump MH, Jann AE, Lanham DC (2003) Specificity of cerebellar vermian abnormalities in autism: a quantitative MRI study. J Child Neurol 18: 463-470.
Jarrar MH, Danko CG, Reddy S, Lee Y-J M, Bibat G, Kaufmann WE (2003) MeCP2 expression in human cerebral cortex and lymphoid cells: immunochemical characterization of a novel higher molecular weight form. J Child Neurol 18: 675-682.
Kau ASM, Tierney E, Bukelis I, Stump MH, Kates, Trescher WH, Kaufmann WE (2004) Social behavior profile in young males with Fragile X syndrome: characteristics and specificity. Am J Med Genet 126A: 9-17.
Kaufmann WE, Jarrar MH, Wang JS, Lee Y-JM, Reddy S, Bibat G, Naidu S (2004) Histone modifications in Rett syndrome lymphocytes: a preliminary evaluation. Brain Dev: in press. |
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koliat@jhmi.edu |
| Phone |
(410) 502-5172 |
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Vassilis E. Koliatsos, M.D.
Primary Appointment in Pathology; Secondary Appointments in Neurology, Neuroscience, Psychiatry
Member, Graduate Program in Neuroscience; Member, Graduate Program in Pathobiology
My main interest is mechanisms of traumatic and degenerative brain injury and repair. I have taken a pathophysiological approach to these problems, i.e. viewing pathology as an inappropriate misplaced or excessive version of a physiological process. For example, programmed cell death is a pivotal developmental mechanism for organism and organ formation, but excessive cell death signaling can cause neurodegenerative diseases such as Alzheimers disease (AD) and Amyotrophic Lateral Sclerosis (ALS). In a series of papers in the early and mid-90s, work in the lab characterized a number of neurotrophic peptides for key populations of neurons in the brain and spinal cord. We also demonstrated the role of programmed cell death in an index neurodegenerative disorder, i.e. Huntingtons disease.
I have recently turned my attention to cellular therapies for degenerative and traumatic diseases of the nervous system, i.e. applications involving embryonic and neural stem cells. We have worked on several lines of neural stem cells and have recently published pivotal studies showing efficacy of stem cell grafts in animal models of ALS. Although a lot of my previous work has focused on the more accessible peripheral motor system, I am now working to apply some of the lessons from this research to neocortical and limbic circuits implicated in memory and complex behaviors. To this effect, I have begun to characterize the role of small GABAergic cortical interneurons that serve as sensors of injury and may be actively engaged in both scavenging injured pyramidal neurons and laying the groundwork for ongoing cueing of neurons that emerge from existing neurogenic niches of the adult brain.
Publications
Yan J, Welsh AM, Xu L, Johe K and Koliatsos VE: Large-scale survival, differentiation and structural integration of human neural stem cells grafted into the adult rat spinal cord. PLoS Medicine 4(2), 2007: e39 doi:10.1371/journal.pmed.0040039
Yan J, Xu L, Welsh AM, Chen D, Hazel T, Johe K, and Koliatsos VE: Combined Immunosuppressive Agents or CD4 Antibodies Prolong Survival of Human Neural Stem Cell Grafts and Improve Disease Outcomes in Amyotrophic Lateral Sclerosis Transgenic Mice. Stem Cells 24:1976-1985, 2006.
Xu L, Yan J, Chen D, Welsh AM, Hazel T, Johe K, Hatfield G, and Koliatsos VE: Human Neural Stem Cell Grafts Ameliorate Motor Neuron Disease in SOD-1 Transgenic Rats. Transplantation 82:865-875, 2006.
Nasonkin IO, Koliatsos VE: Nonhuman sialic acid Neu5Gc is very low in human embryonic stem cell-derived neural precursors differentiated with B27/N2 and noggin: Implications for transplantation. Exp. Neurology 201:525-529, 2006.
Koliatsos,VE, Kecojevic,A, Troncoso,JC, Gastard,MC, Bennett,DA, Schneider,JA: Early involvement of small inhibitory cortical interneurons in Alzheimer's disease. Acta Neuropathologica 112:147-162, 2006.
Zhou Y, Zhou L, Chen H and Koliatsos VE: An AMPA glutamatergic receptor activation-nitric oxide synthesis step signals transsynaptic apoptosis in limbic cortex. Neuropharmacology 51(1):67-76, 2006.
Koliatsos VE, Dawson TM, Kecojevic A, Zhou Y, Wang Y-F, and Huang K-X: Cortical interneurons become activated by deafferentation and instruct the apoptosis of pyramidal neurons. PNAS 101:14264-14269, 2004. |
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tli1@jhmi.edu |
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(410) 502-5189 |
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Tong Li, Ph.D.
Primary Appointment in Pathology
Temporary Text
Publications
Temporary Text |
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| Email |
martinl@jhmi.edu |
| Phone |
(410) 502-5170 |
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Lee J. Martin, Ph.D.
Primary Appointment in Pathology; Secondary Appointment in Neuroscience
Member, Graduate Program in Neuroscience; Member, Graduate Program in Pathobiology
Mechanisms of Neuronal Death in Adult and Developing Central Nervous System. In the human central nervous system (CNS), neurons degenerate after acute neurological insults resulting from stroke and cardiac arrest and during the progression of adult-onset neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. Only certain groups of neurons degenerate in each of these neurological disorders, and this phenomenon is called selective vulnerability. In order to therapeutically manage and prevent this neurodegeneration, it is important to identify the cellular and molecular mechanisms of selective neuronal vulnerability and death. In my laboratory, we are testing the hypothesis that selective vulnerability is dictated by brain regional connectivity, mitochondrial function, and oxidative stress and is mediated by excitotoxic cell death resulting from abnormalities in excitatory, glutamatergic signal transduction pathways, including glutamate transporters and glutamate receptors as well as their downstream intracellular signaling molecules. We are also investigating the contribution of neuronal/glial apoptosis and necrosis as cell death pathways in animal (including transgenic mice) models of acute and progressive neurodegeneration. We use a variety of anatomical and molecular neurobiological approaches, including neuronal tract-tracing techniques, immunocytochemistry, immunoblotting, antipeptide antibody production, transmission electron microscopy, and DNA analysis to determine the precise regional and cellular vulnerabilities and the synaptic and molecular mechanisms that result in selective neuronal degeneration.
Publications
Martin LJ: Neuronal cell death in nervous system development, disease, and injury. Int. J. Mol. Med. 7: 455-478, 2001.
Martin LJ and Liu Z: Injury-induced spinal motor neuron apoptosis is preceded by DNA single-strand breaks and is p53- and bax-dependent. J. Neurobiol. 50: 181-197, 2002 (Journal Cover Illustration).
Lesuisse C and Martin LJ: Immature and mature cortical neurons engage different apoptotic mechanisms involving caspase-3 and the mitogen-activated Protein kinase pathway. J Cereb. Blood Flow Metab. 22: 935-950, 2002.
Martin LJ, Price AC, McClendon KB, Al-Abdulla NA, Subramaniam JR, Wong PC and Liu Z: Early events of target deprivation/axotomy-induced neuronal apoptosis in vivo: oxidative stress, DNA damage, p53 phosphorylation and subcellular redistribution of death proteins. J. Neurochem. 85: 234-247, 2003. |
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Carlos A. Pardo-Villamizar, M.D.
Primary Appointment in Neurology; Secondary Appointment in Pathology
The research activities of our laboratory (Neuroimmunopathology Lab) are focused on studies of immunopathological mechanisms of disease in neurological disorders. Our main areas of interest include neurological problems associated with HIV infection, epilepsy, autism and multiple sclerosis/transverse myelitis. We have established an extensive repository of central and peripheral nervous system tissues from clinically characterized HIV-associated neurological disorders such as HIV dementia, vacuolar myelopathy, peripheral neuropathy as well as neuroimmunological disorders. The main focus of research is the characterization of the immunopathogenic mechanisms by morphological, immunocytochemical and molecular techniques and the development of animal models of disease. Ongoing projects and specific areas of research include studies of the role of chemokine and chemokine receptors in neurological disorders, the immunopathology of HIV neurological complications, studies of epilepsy and seizure disorders mediated by immunological factors such as Rasmussen's syndrome, autism spectrum disorders and animal models of neurological disorders. Our laboratory research has been funded through the National Institutes of Health, Cure Autism Now (CAN) and The Epilepsy Foundation of America.
Publications
Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with
autism. Ann Neurol 2004;DOI 10.1002/ana.20315.
Pardo CA, Vining EP, Guo L, Skolasky RL, Carson BS, Freeman JM. The pathology of Rasmussen syndrome: stages of cortical involvement and
neuropathological studies in 45 hemispherectomies.
Epilepsia. 2004 May;45(5):516-26.
Pardo CA, McArthur JC, Griffin JW. HIV neuropathy: insights in the pathology of HIV peripheral nerve disease. J Peripher Nerv Syst. 2001 Mar;6(1):21-7. Review.
Pardo CA and Gartner S. Neuroimmunopathology of HTLV 1 associated myelopathy. In Dangond F. (Ed). Disorders of myelin in the central and peripheral nervous system. Butterworth Heinnemann, Woburn, MA. 2002, pp259-270.
Han Y, He T, Huang DR, Pardo CA, Ransohoff RM: TNF alpha mediates SDF1alpha induced NF kappa B activation and cytotoxic effects in primary astrocytes. J Clin Invest 2001, 108:425-435. |
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| Email |
troncoso@jhmi.edu |
| Phone |
(410) 502-5165 |
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Juan C. Troncoso, M.D.
Primary Appointment in Pathology; Secondary Appointment in Neurology
Member, Graduate Program in Pathobiology
My research activities focus on the neuropathology, pathogenesis and therapy of neurodegenerative disorders, i.e. Alzheimer's, Parkinson's, and Huntington's disease, and the neuropathology of aging. These activities encompass morphological studies of human brains and clinical-pathological correlations, along with investigations of the pathogenesis of neurodegenerative disorders in relevant genetically engineered mouse models and in vitro systems. These research activities are funded by the JHU Alzheimer's Disease Research Center (NIA), Morris K. Udall Parkinson's Disease Center of Excellence (NINCDS), the Huntington's Disease Center (NINCDS).
Studies of human brain include detailed clinical-pathological correlations on diseased and control subjects who have had thorough neurological and cognitive assessments. In recent years, my collaborators and I have begun to define the early stages of Alzheimer's Disease (AD), including preclinical and mild cognitive impairment (MCI) stages. Using unbiased stereology approaches, a particular strength of my laboratory, we have shown that the number of neurons of the hippocampus remains stable in preclinical AD.
Investigations of AD immunotherapy, funded by a grant of the Alzheimer's Association, represent a new and very exciting field of research in my laboratory. In collaboration with my colleague David Borchelt, Ph.D., we are studying the effects of immunization with A-beta or the passive transfer of A-beta antibodies in transgenic mouse models of AD. This investigation has several facets that include the development of new vaccine formulations to reduce the risk of encephalomyelitis, neuropathological and behavioral assessments, and investigations of the mechanisms underlying the beneficial effects of A-beta immunization on A-beta deposition and cognitive/behavioral performance of affected animals.
Publications
West MJ, Coleman PD, Flood DG, Troncoso JC. Differences in the pattern of hippocampal neuronal loss in normal aging and Alzheimer's disease. Lancet 344:769-772, 1994.
Troncoso JC, Martin LJ, Dal Forno G, Kawas CH. Neuropathology in controls and demented subjects from the Baltimore Longitudinal Study of Aging. Neurobiol. Aging 17:365-371, 1996.
Vehmas AK, Borchelt DR, Price DL, McCarthy D, Wills-Karp M, Peper M, Rudow G, Luyinbazi J, Siew L, Troncoso J. Beta-amyloid peptide vaccination results in marked changes in serum and brain A-beta levels in APPswe/PS1E9 mice, as detected by SELDI-TOF-based ProteinChip® technology. DNA and Cell Biology 20:713-721, 2001.
West MJ, Kawas CH, Stewart WF, Rudow GL, Troncoso JC. Hippocampal neurons in pre-clinical Alzheimers disease. Neurobiology of Aging 25(9):1205-12, 2004.
Pletnikova O, West N, Lee MK, Rudow G, Skolasky RL, Dawson TM, Marsh L, Troncoso JC. Aβ deposition enhances cortical α-synuclein lesions in Parkinsons disease. Accepted for publication in Neurobiology of Aging.
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WONG@jhmi.edu |
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(410) 502-5168 |
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Philip C. Wong, Ph.D.
Primary Appointment in Pathology; Joint Appointment in Neuroscience
Member, Graduate Program in Cellular and Molecular Medicine; Member, Graduate Program in Neuroscience; Member, Graduate Program in Pathobiology
My research program is designed to understand the molecular mechanisms of neurodegenerative diseases, particularly Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). A major pathological hallmark of AD is the deposition of a toxic peptide, termed beta-amyloid (Ab) that is liberated from a parental beta-amyloid precursor protein (APP) by two enzymatic cleavages, termed beta- and gamma-secretase. We have previously hypothesized that beta-secretase (also called BACE1), enriched in neurons of the central nervous system (CNS), is a major determinant that predisposes the brain to Abeta amyloidogenesis and demonstrated that the physiologically high levels of BACE1 activity coupled with low levels of BACE2 and beta-secretase activities in neurons are major contributors to the accumulation of Abeta in the CNS while other tissues and organs are spared. Significantly, deletion of BACE1 in APPswe; PS1dE9 mice prevents Ab deposition. Moreover, deletion of BACE1 restored age-associated cognitive abnormalities that occur in this model of Ab amyloidosis. Recently, we have begun efforts to develop inducible mouse models of BACE1 or RNAi approaches to suppress expression of BACE1 in models of amyloidosis in order to examine issues regarding the reversibility of Ab deposition on brain repair. It has been shown that the presenilins (PS1 and PS2), which when mutated cause familial AD, participate in the intramembraneous proteolysis of several type I transmembrane proteins, including APP and Notch1. The current view is that the gamma-secretase complex is comprised of at least PS, Nicastrin, APH-1 and PEN-2. Our deletion analyses of PS1, Nicastrin and Aph-1 established that each of these membrane proteins is an essential component of the gamma-secretase complex. Current studies are aimed towards defining the exact role for each of these components in complex assembly and activity of this interesting enzyme complex as well as testing their therapeutic potentials as drug targets for AD.
Recently, missense mutations have been linked to the p150 subunit of the dynactin complex in ALS. The dynactin complex is a high molecular weight multi-protein complex that was originally shown to differentially co-purify with dynein, the molecular motor responsible for retrograde transport along microtubules. Defects in axonal transport have been proposed as a possible pathogenic mechanism in ALS. Since mutant dynactin is inherited in an autosomal dominant fashion, we hypothesize that the disease mechanism is associated with an adverse gain of function. To test whether the G59S mutant p150 subunit of the dynactin complex is sufficient to confer motor neuron disease in mice, we generated mutant p150 transgenic mouse models. This mouse model should be invaluable to clarify whether defects in axonal transport can be an important pathogenic mechanism in ALS.
Publications
Ma G, Li T, Price DL and Wong PC: Aph-1a is the principal mammalian Aph-1 isoform present in gamma-secretase complexes during embryonic development. J. Neuroscience, in press.
Li T, Ma G, Cai H, Price DL, Wong PC: Nicastrin is required for assembly of presenilin/gamma-secretase complexes to mediate Notch Signaling, and for processing and trafficking of beta-APP in mammals. J. Neuroscience 23: 3272-3277, 2003.
Subramaniam JR, Lyons WE, Liu J, Bartinakas TB, Rothstein J, Price DL,Cleveland DW, Gitlin JD and Wong PC: Mutant SOD1 causes motor neuron disease independent of copper chaperone-mediated copper loading. Nature Neuroscience 5: 301-307, 2002.
Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL and Wong PC: BACE1 is the major beta-secretase for generation of Ab peptides by neurons. Nature Neuroscience 4: 233-234, 2001.
Wong PC, Zheng H, Chen H, Becher MW, Sirinathsinghji DJS, Trumbauer ME, Chen HY, Price DL, Van der Ploeg LHT and Sisodia SS: Presenilin 1 is required for Notch1 and Dll1 expression in the paraxial mesoderm. Nature 387: 288-292, 1997. |
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