Anaplastic gliomas are highly malignant tumors that have remained resistant to most forms of treatment. This resistance is in part related to the ability of these tumors to invade normal brain. This greatly limits the efficacy of local measures, such as surgery or radiation therapy, to eradicate this disease. Malignant gliomas invade normal brain by moving along the extracellular matrix, in a process based on amoeboid motion. This motion requires the coordination of two components-a """"""""motor"""""""" to provide propulsive force, and a set of """"""""anchors"""""""" that the cell membrane can use to attach to and detach from the extracellular matrix as it crawls along. The protein myosin is the """"""""motor"""""""" for most forms of cell motility, and integral membrane proteins called integrins function as the anchors. These proteins thus represent potential targets for the pharmacologic manipulation of glioma motility and invasiveness. Data to be presented in this application will show that myosin II, the major isoform of myosin in non-muscle cells, is present in gliomas. I will propose in this application to study the role of second messengers, including protein kinase C and myosin light chain kinase, in regulating myosin filament assembly and glioma invasiveness. I will then examine the effects of pharmacologic inhibitors of these second messengers on myosin filament assembly and on glioma morphology and invasiveness. Finally, I will examine the effect of small protein antagonists of integrin function, called """"""""disintegrins"""""""" on glioma attachment to and invasion through extracellular matrix and will initiate a study of the solution structure of glioma-active disintegrins. Results of these studies may ultimately allow the development of new pharmacologic modulators of cell motility that could alter the biological aggressiveness of malignant glial tumors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory Grants (P20)
Project #
1P20NS031096-01
Application #
3847174
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Type
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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