Malignant brain tumors represent one of the most refractory cancers to therapy and remain incurable. Gliomas represent the most common type of brain tumors occurring in various grades, with the patients' prognosis inversely proportional to the grade. The long-term objective of Dr. Rao is to understand the cellular and molecular mechanisms that underlie tumor invasiveness in human gliomas. He has been active in the study of proteases and the biology of brain tumors, and data generated so far have indicated that changes in proteases are correlated with the changes in the grade of the tumors. The hypotheses to be tested in this project are: 1) The malignant phenotype and the invasive behavior of the various grades of human gliomas is determined, in part, by the mRNA stability and promoter activity of cathepsin B. 2) The modulation of cathepsin B expression will provide an inhibitory effect on the invasive behavior of human gliomas.
The Specific Aims are: 1) Determine the overexpression of cathepsin B in glioma cells: In this Specific Aim, he will determine whether cathepsin B overexpression in cultured gliomas cells is a consequence of the stability of mRNA and/or transcriptional activation of the gene. 2) Determine the modulation of cathepsin B on the invasive phenotype of gliomas cells in vitro and in vivo: He will first examine the effect of an antisense cathepsin B expression vector on the invasive phenotype of established gliomas cells and determine the invasive behavior of these stable transfectants both in vivo and in vitro. Next, he will transfect low-level or deficient cathepsin B producing glioma cells with a full-length cathepsin B and study the invasive behavior of these stable transfectants both in vitro and in vivo. The results of these studies will strengthen the understanding of the role of cathepsin B in the biologic behavior of the tumors and that determination/modulation of the molecular mechanisms that underscore the over expression of cathepsin B could lead to the development of novel anti-invasive therapeutic avenues.
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