The long-term goal is to develop drugs that correct deficiencies in the regulation of oxygen radical production by phagocytes. Oxygen radicals are essential for efficient killing of pathogens, but inappropriate release of oxygen radicals can result in tissue damage. The pathogenicity of some microbes is due, in part, to their ability to interfere with the phagocytes' production of oxygen radicals. Regulation of oxygen radical production is a two-stage process, involving """"""""activation"""""""" and """"""""triggering."""""""" The first specific aim is to examine the biochemical mechanisms responsible for the activation of macrophages. Based on preliminary experiments, the following hypothesis will be tested: The enzyme that produces oxygen radicals, NADPH oxidase, has a component, cytochrome b, which moves from a storage location in granules to its site of action in the plasma membrane. The extent of this movement determines the potential activity of NADPH oxidase and therefore the state of activation of the macrophage. There is a regulatory protein in the macrophage plasma membrane that keeps the macrophage in a non-activated or """"""""resident"""""""" state, by blocking the incorporation of cytochrome b into the plasma membrane. Cleavage of this protein by external protease results in activation. The second specific aim is to examine whether macrophage activation can cure experimental infections in mice. Drugs that cause macrophage activation, including recombinant gamma interferon and interleukin 2, muramyl dipeptide and indomethacin, will be given to mice infected with the chromic intracellular pathogen, Mycobacterium intracellulare. The reduction in the numbers of infection micro-organisms and the effect of the drugs on the microbicidal activity of the macrophages will be studied. The third specific aim is to examine the effectiveness of macrophage activating agents on the microbicidal activity of cultured human monocytes. Monocytes taken from patients with chronic mycobacterial infection will be treated with the drugs to determine whether the function of these monocytes can be improved. The effectiveness of muramyl dipeptide and gamma interferon in treating monocytes from patients who have mycobacterial infections as a result of AIDS will be tested. These macrophage activators should be able to bypass the defective T-lymphocyte function in AIDS patients. Ultimately, the knowledge and the drugs developed here might aid human patients to resist periodontal disease and other chronic diseases resulting from infection or from deficiencies in the immune system.
| Beranova-Giorgianni, Sarka; Pabst, Michael J; Russell, Tara M et al. (2002) Preliminary analysis of the mouse cerebellum proteome. Brain Res Mol Brain Res 98:135-40 |
