""""""""The goal of the laboratory is to develop new approaches to the diagnosis and management of infectious complications in children with neoplastic diseases and HIV infection. A major focus of the laboratory has been to investigate the NADPH-oxidase, a multi-component enzyme system, primarily restricted to phagocytic cells. The NADPH-oxidase is responsible for the generation of oxygen radicals, critical to microbicidal and possibly, anti-tumor activity. Study of a rare, inherited disease, chronic granulomatous disease, in which patients are characterized by a defective NADPH-oxidase, has been especially useful for elucidating the regulation and assembly of the NADPH-oxidase complex. We have concentrated our efforts on characterizing the gene structures and regulation of three cytosolic components, p40-phox, p47-phox and p67-phox. We have shown that NADPH-oxidase activity modulates the topoisomerase I mediated apoptosis pathway in neutrophils and human leukemia cell lines. We have investigated the influence of variant forms of molecules of innate immunity on disease susceptibility and outcome in immunocompromised patients. Under the stress of losing a major component of host defense (i.e., neutropenia or an absent respiratory burst), observed differences in phenotypic expression of disease may be related to polymorphisms in either a regulatory or structural region of primitive immune molecules, such as cytokines, Fc receptors, lectins and interleukins. For each gene chosen for study, at least one or more polymorphisms are known to exist which influence either the level or functional activity of the molecule. Specifically, we have shown that variant genotypes of the myeloperoxidase, Fcgamma receptors 2a and 3b genes have been associated with immunologically mediated complications of CGD. Rheumatologic conditions have been associated with variant genotypes of FcR2a and MBL2. In addition, this study establishes a foundation for investigating other candidate loci in CGD and can readily be applied to other cohorts with cancer, HIV or a primary immunodeficiency in which the clinical endpoints are well characterized. We have also concentrated on analyzing variant alleles of at least twenty different molecules of innate immunity in a large, healthy control population. For example, we have shown that the highly related Fcgamma receptor polymorphisms show random distribution in two control populations, a notable finding in anticipation of studies designed to evaluate multiple loci in the same population. This approach is critical for identifying possible genetic risk factors but also yields important observations that bear further in vitro analysis and lead to new insights in disease pathogenesis. The long-range goal of genetic annotation studies is to identify potential gentoypic differences that may bear important predictive value for infectious complications of disease (and perhaps other therapy related toxicities). HIV/AIDS 30%""""""""
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