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.
