Kaposi's sarcoma (KS) is a multifocal vascularized tumor and the most frequent tumor arising in HIV-infected patients. Both the HIV-1 transactivator protein Tat, and the KS associated Herpesvirus (KSHV) contribute directly to the pathogenesis of AIDS-KS. Previous studies, and our own preliminary data, suggest that the constitutively active KSHV-G protein-coupled receptor (vGPCR) induces KS lesions. However, the molecular mechanisms by which Tat and vGPCR lead to the development of these lesions are not clearly understood. There is a need to develop a relevant animal model system of AIDS-KS to test the combine effects of HIV-1/KSHV genes in vivo. We hypothesize that the accumulation of HIV-Tat in endothelial cells (EC) enhances the growth promoting activity of vGPCR, and induces KS tumors. A second corollary of this hypothesis is that the simultaneous in vivo expression of vGPCR and Tat in mouse EC will generate a clinically relevant small animal model system of AIDS-KS.
Two specific aims will be study:
AIM 1) To develop a new transgenic (Tg) mouse model of AIDS-KS, and determine whether the simultaneous in vivo expression of vGPCR and Tat in mouse EC leads to rapid development of AIDS-KS tumors. We will generate a dual Tg mouse model expressing HIV-tat and the avian leukosis virus (ALV)-receptor, TVA, both under the control of the EC-specific TIE2 promoter. This system enables EC specific infection in vivo by using AVL-derived retroviruses encoding vGPCR.
AIM 2. To identify relevant molecular pathways by which vGPCR and Tat promote the growth of AIDS-KS tumors in vivo, using genome-wide profiling methods and Affymetrix arrays in skin KS tumors. Here, we will identify the most relevant angiogenic signaling pathways activated/suppressed by vGPCR and Tat, alone or in combination, throughout 3 different stages of KS development. Positive findings will be validated in AIDS-KS sections from dual Tg mice and HIV-infected patients. Overall, these studies will generate a new mouse model of AIDS-KS that should facilitate the systematic examination of the role of putative KSHV oncogenes, in combination with HIV-1 genes, and could be used for developing new molecular-based diagnostics and therapeutic against this deadly disease. ? ? ?
| Jerebtsova, Marina; Wong, Edward; Przygodzki, Ronald et al. (2007) A novel role of fibroblast growth factor-2 and pentosan polysulfate in the pathogenesis of intestinal bleeding in mice. Am J Physiol Heart Circ Physiol 292:H743-50 |
