With marijuana use on the rise in America, it is essential to define the health risks associated with this drug The primary goals of this proposal are to identify the toxic and carcinogenic effects of marijuana on the respiratory tract, and to identify the mechanisms by which tetrahydrocannabinol (delta9-THC) suppresses cellular immunity and the responses to cancer and HIV. We propose three specific aims.
The first aim i s to characterize the genetic injury and molecular dysregulation that occurs in the bronchial mucosa of marijuana smokers. Bronchoscopy will be performed on marijuana and/or tobacco smokers and lung biopsies analyzed for the presence of oncogene activation by immunohistochemical techniques (for EGFR, Ki-67, K-ras, and p53). Samples with alterations in the expression of K-ras and p53 will be further analyzed by PCR to determine the presence and type of mutation occurring in the genes coding for these products. Finally, to delineate the pathways mediating these mutations, the pattern and extent of cytochrome P4501AI activation, and of DNA adduct damage, will be compared between groups.
In aim #2, we will determine the capacity for marijuana tar to injure lung epithelial cells and to activate genes involved in cell injury and carcinogenesis. Using a smoking device, tar extracts will be prepared and tested in a variety of cell injury assays. Marijuana tar will also be checked for its ability to directly activate genes associated with cell injury and repair. Finally, in aim #3, we will investigate the effects of purified delta9-THC on the immune response to cancer and HIV. The ability for antigen-presenting dendritic cells to stimulate purified T cells will be evaluated in the presence and absence of delta9-THC. The effects on T cell proliferation and T-helper type I (THI) versus T-helper type 2 (TH2) cytokine production will be determined. Using a murine model of lung cancer, delta9-THC will also be evaluated for its effects on tumor growth and the animal's immune response to cancer. The effects of marijuana on the infectivity and replication of HIV will be determined in vitro and lung macrophages that have been infected with HIV will be tested for immunosuppression mediated by exposure to delta9-THC in culture.
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