Candidate: The Principal Investigator of this Research Career Award is an Assistant Professor of Neurosurgery at the University of Pittsburgh. The purpose of this K08 award is to provide the PI with sufficient training in molecular biology to transition from a mentored to an independent clinician scientist. Both the Pl's research interests and clinical practice focus on translational brain tumor research. Environment: Research will be performed at the University of Pittsburgh, within laboratory space dedicated to the PI, augmented by resources and space provided by the project mentor. Project collaborators are drawn from the University of Pittsburgh and outside institutions. The training plan involves formal training in bioinformatics, molecular biological techniques, animal models of cancer, and translational research. Research Plan: The project will identify glioma endothelial marker genes (GEMS) that are up-regulated in brain endothelium in response to signaling from brain tumors. Candidate GEMS are identified through Serial Analysis of Gene Expression (SAGE), a quantitative technique to measure mRNA expression levels, on endothelial cells purified from clinical brain tumor and normal brain specimens. Candidate GEMS determined from SAGE are further examined against a panel of representative human brain tumor specimens using in situ hybridization and immunohistochemistry. GEMS that are up-regulated within the endothelium across a spectrum of brain tumors are investigated for biological relevance. GEMS expression is quantitatively assessed using 3-D fibrin gel models of in vitro angiogenesis and in vivo using human brain tumor xenografts in athymic mice. Using these models, expression of individual GEMS are silenced using expression plasmids coding for short-hairpin RNA (shRNA) targeted against the gene of interest. The biologic response to GEMS inhibition is measured by MTT assay, TUNEL, microtubule formation, tumor xenograft growth, and vascular index. GEMS whose inhibition blocks angiogenesis are suitable for preclinical testing as gene therapy targets using the shRNA constructs developed as part of the project or as targets for small molecule inhibitors. In this fashion, using bioinformatics and high throughput screening, the project will elucidate new genes (GEMS) associated with brain tumor angiogenesis and rapidly adapt these discoveries to design novel therapies for malignant glioma. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS046461-02
Application #
6884679
Study Section
NST-2 Subcommittee (NST)
Program Officer
Fountain, Jane W
Project Start
2004-04-15
Project End
2009-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
2
Fiscal Year
2005
Total Cost
$176,969
Indirect Cost
Name
University of Pittsburgh
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Liu, Yang; Carson-Walter, Eleanor; Walter, Kevin A (2015) Targeting chemokine receptor CXCR7 inhibits glioma cell proliferation and mobility. Anticancer Res 35:53-64
Gabikian, Patrik; Tyler, Betty M; Zhang, Irma et al. (2014) Radiosensitization of malignant gliomas following intracranial delivery of paclitaxel biodegradable polymer microspheres. J Neurosurg 120:1078-85
Liu, Yang; Carson-Walter, Eleanor; Walter, Kevin A (2014) Chemokine receptor CXCR7 is a functional receptor for CXCL12 in brain endothelial cells. PLoS One 9:e103938
Liu, Yang; Carson-Walter, Eleanor B; Cooper, Anna et al. (2010) Vascular gene expression patterns are conserved in primary and metastatic brain tumors. J Neurooncol 99:13-24
Carson-Walter, Eleanor B; Winans, Bethany N; Whiteman, Melissa C et al. (2009) Characterization of TEM1/endosialin in human and murine brain tumors. BMC Cancer 9:417
Shue, Eveline H; Carson-Walter, Eleanor B; Liu, Yang et al. (2008) Plasmalemmal vesicle associated protein-1 (PV-1) is a marker of blood-brain barrier disruption in rodent models. BMC Neurosci 9:29
Carson-Walter, Eleanor B; Hampton, Jessica; Shue, Eveline et al. (2005) Plasmalemmal vesicle associated protein-1 is a novel marker implicated in brain tumor angiogenesis. Clin Cancer Res 11:7643-50