The objectives of this competing renewal application is to continue to investigate the mechanisms associated with drug-induced hematological toxicity in AIDS therapy. The hematological toxicity of zidovudine (AZT) remains a limiting factor in clinical management of AIDS and is often the single most important complication ultimately requiring cessation of therapy. In addition, impaired hematopoiesis is also one of the major abnormalities associated with HIV-1 infection. The preliminary data included in this application would suggest that the trans-activator protein (Tat) of HIV-1 may down regulate gamma-globin gene expression in hematopoietic progenitor cells and also may enhance AZT-induced inhibition of erythroid differentiation. The Principal Investigator, therefore, hypothesizes that a combination of cellular and molecular effects caused by HIV-1 TAT together with drug- induced effects may lead to an enhanced hematopoietic toxicity. To test this hypothesis, he proposes: (1) to study the role of Tat-induced myelosuppression in enhancing the AZT and other 2',3'-dideoxynucleoside (ddN)-induced inhibition of hematopoietic differentiation in human hematopoietic cell line (K-562) and in human bone marrow CD34+ cells; (2) to examine the effect of Tat on transmembrane signalling by erythropoietin (EPO)-EPO receptor complex involving tyrosine phosphorylation and protein kinase C during proliferation and differentiation of erythroid progenitor cells; (3) to determine the role of TAT-induced cytokines, TNF alpha and beta and TGF beta, in the microenvironment of human mixed bone marrow cells, in modulating differentiation in the presence and absence of AZT and other ddNs; (4) to determine the role of Tat on the expression of proto-oncogenes c-myc, c-fos, and c-raf in the progenitor cells in the presence and absence of AZT; (5) to examine the effects of Tat and/or AZT on apoptosis in progenitor cells by monitoring DNA fragmentation and utilizing video imaging techniques; and 6) to develop new therapeutic approaches to overcome the HIV-1 Tat and AZT-induced bone marrow toxicity based upon the underlying mechanisms. In completing these specific aims, the Investigator to gain an in-depth understanding of the mechanisms associated with hematological toxicity in AIDS patients, and a basis for development of effective therapeutic approaches to overcome the hematological suppression.
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