The objective of the following research program is to develop the candidate into an independent biomedical investigator in the area of brain tumor research. The candidate's clinical training in Anatomic Pathology and Neuropathology, and his past research experience the field of glial cell biology, provide a firm foundation on which to build a career devoted to basic research on human disease. The diverse clinical and basic science research programs at Columbia Presbyterian Medical Center, especially in the field of Neuroscience, provide an excellent environment in which the candidate can interact and establish collaborations and develop as an independent researcher and physician. Human gliomas, including glioblastomas, astrocytomas and oligodendrogliomas, have a remarkable capacity to infiltrate the brain, making complete surgical resection impossible. Glioma cell migration is not random, but rather follows preferred paths, such as along blood vessels and myelinated fiber tract. Our goal is to understand the molecular mechanisms that regulate glioma migration. Towards this end, we have developed an experimental system to monitor glioma cells migrating in living slices of rodent brain using time-lapse videomicroscopy. We are using this system, in combination with a variety of well established in vitro migration assays, to test the effects of specific guidance molecules on glioma migration. Our initial analysis is focused on a group of molecules called Eph receptors and their binding partners the ephrins. Eph-ephrin signaling mediate repulsive interactions that guide migrating cells during embryonic development. We hypothesize that these molecules play a similar role in glioma migration. To test this we will interfere with Eph-ephrin signaling using molecular and pharmacological techniques and then measure the effects on glioma migration in two different rodent glioma models. The first model uses stereotactic transplantation of genetically modified glioma cells (C6-GFP) into rodent forebrain. The second model uses avian retroviral vector(s) to deliver oncogenes selectively into glial progenitors via infection of transgenic mice that express the avian retrovirus receptor (t-va) from specific promoters. We will first characterize the expression of Ephs and ephrins in these models and then combine these animal models with in vitro and ex vivo migration assays to study how interfering with Eph-ephrin signaling effects glioma migration.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS045070-03
Application #
6915632
Study Section
NST-2 Subcommittee (NST)
Program Officer
Fountain, Jane W
Project Start
2003-06-01
Project End
2008-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
3
Fiscal Year
2005
Total Cost
$174,533
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Massey, Susan Christine; Assanah, Marcela C; Lopez, Kim A et al. (2012) Glial progenitor cell recruitment drives aggressive glioma growth: mathematical and experimental modelling. J R Soc Interface 9:1757-66
Kennedy, Benjamin C; Maier, Lisa M; D'Amico, Randy et al. (2009) Dynamics of central and peripheral immunomodulation in a murine glioma model. BMC Immunol 10:11
Assanah, M C; Bruce, J N; Suzuki, S O et al. (2009) PDGF stimulates the massive expansion of glial progenitors in the neonatal forebrain. Glia 57:1835-47
Cayre, Myriam; Canoll, Peter; Goldman, James E (2009) Cell migration in the normal and pathological postnatal mammalian brain. Prog Neurobiol 88:41-63
Ivkovic, Sanja; Canoll, Peter; Goldman, James E (2008) Constitutive EGFR signaling in oligodendrocyte progenitors leads to diffuse hyperplasia in postnatal white matter. J Neurosci 28:914-22
Canoll, Peter; Goldman, James E (2008) The interface between glial progenitors and gliomas. Acta Neuropathol 116:465-77
Beadle, Christopher; Assanah, Marcela C; Monzo, Pascale et al. (2008) The role of myosin II in glioma invasion of the brain. Mol Biol Cell 19:3357-68
Assanah, Marcela; Lochhead, Richard; Ogden, Alfred et al. (2006) Glial progenitors in adult white matter are driven to form malignant gliomas by platelet-derived growth factor-expressing retroviruses. J Neurosci 26:6781-90
Farin, Azadeh; Suzuki, Satoshi O; Weiker, Michael et al. (2006) Transplanted glioma cells migrate and proliferate on host brain vasculature: a dynamic analysis. Glia 53:799-808