Research Description:
The expression of hypoxia-inducible factor-1α (HIF-1α) has been shown to increase in higher-grade gliomas such as glioblastoma multiforme (GBM). This grade specific overexpression has implicated HIF-1α as a necessary factor for tumor growth and development. Under normal physiological conditions HIF-1α regulates expression of vascular endothelial growth factor (VEGF) and glycolysis, both of which are proposed to elevate during tumorigenesis. Though there have been reports disputing its role as a tumor suppressor, it is proposed that a decrease in HIF-1α expression could lead to a reduction of tumor growth and angiogenesis.
RNA Interference (RNAi) is a conserved mechanism of regulating gene expression in organisms ranging from plants to mammals. While RNAi is mostly noted for accelerating the understanding of many gene functions in vivo, it also has the therapeutic potential to treat many challenging diseases by gene specific silencing. In previous work in our lab, RNAi directed against HIF-1α in a flank tumor model not only demonstrated a reduction of HIF-1α expression but reductions in tumor volume, VEGF and GLUT-1 expression as well. Other researchers have found that a knockdown cell model of HIF-1α showed only attenuation of astrocytomas in the flank region but not intracranially. This study questions the validity of tumor flank models due to their relatively unvascularized growth environment and we believe that further analysis of RNAi directed reduction of HIF-1α is needed in an intracranial tumor model.
Because the overall goal of this study is to eventually use this RNAi for clinical application, the focus will be on injected forms of HIF-1α directed siRNAs complexed to a novel multifunctional carrier, which will allow for easy administration and non-permanent disruption of the cell’s DNA. Recognizing that in vivo delivery of siRNA is often challenging, we also propose to test a newly developed nucleic acid carrier that combines the benefits of the this novel carrier model for both high transfection efficiency and necessary cytoplasm unpackaging.
Does this research involve human subjects or animals? Yes
If yes, what is the protocol number? 07-09008; 09-08007
10/2009
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