Alveolar macrophages play a paramount role in maintaining lung homeostasis. Environmental agents implicated in the etiology of chronic obstructive lung disease have been shown to alter macrophage behavior and these alterations may be critical to the development of the disease. A major mechanism by which macrophages maintain alveolar function is by removing injurious agents. The removal of injurious agents enhanced by the ability of specific surface receptors to bind and internalize extracellular macromolecules. The ability of receptors to be reutilized or recycled provides an efficient mechanism for clearing noxious agents from the lung. In this application we plan to continue our studies on the physiology of macrophage receptors involved in endocytic activity. Using both biochemical and genetic approaches we will define features of the Alpha2macroglobulin protease complex receptor which is necessary for its function. Using somatic cell hybridization we will map the chromosomal location of the AlphaM.P receptor and the receptor for mannose-terminal glycoproteins. Using a negative selection system we will attempt to obtain and analyze mutants defective in endocytosis. Such mutants should lead to insights in the mechanism of recycling. We have demonstrated that the majority of Alphamacroglobulin protease complex and mannose terminal glycoprotein receptors are clustered in coated pits. We wish to extend this analysis to other macrophage receptors such as the transferrin receptor. We also wish to determine the intracellular movement of ligand. In particular we wish to examine intracellular compartments which are intermediate between surface receptor ligand complexes and lysosomes. These compartments contain pools of surface receptors and may be critical to ligand-receptor processing. We propose to analyze intracellular ligand movement by a number of approaches including fluorescence resonance energy transfer and isolation of the intermediate vesicle using anti-receptor antibodies. Finally, we wish to examine whether alveolar macrophages can recycle iron and if such recycling involves transferrin receptors. This latter study will yield insights into the mechanism of pulmonary hemosiderosis. The studies will increase our understanding of the mechanisms of alveolar macrophage membrane dynamics and the role of macrophages in lung disease.
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| White, Carine; Yuan, Xiaojing; Schmidt, Paul J et al. (2013) HRG1 is essential for heme transport from the phagolysosome of macrophages during erythrophagocytosis. Cell Metab 17:261-70 |
| Bagley, Dustin C; Paradkar, Prasad N; Kaplan, Jerry et al. (2012) Mon1a protein acts in trafficking through the secretory apparatus. J Biol Chem 287:25577-88 |
| Durchfort, Nina; Verhoef, Shane; Vaughn, Michael B et al. (2012) The enlarged lysosomes in beige j cells result from decreased lysosome fission and not increased lysosome fusion. Traffic 13:108-19 |
| Paradkar, Prasad N; De Domenico, Ivana; Durchfort, Nina et al. (2008) Iron depletion limits intracellular bacterial growth in macrophages. Blood 112:866-74 |
| Kieffer, Collin; Skalicky, Jack J; Morita, Eiji et al. (2008) Two distinct modes of ESCRT-III recognition are required for VPS4 functions in lysosomal protein targeting and HIV-1 budding. Dev Cell 15:62-73 |
| Kaplan, Jerry; De Domenico, Ivana; Ward, Diane McVey (2008) Chediak-Higashi syndrome. Curr Opin Hematol 15:22-9 |
| De Domenico, Ivana; Ward, Diane McVey; Langelier, Charles et al. (2007) The molecular mechanism of hepcidin-mediated ferroportin down-regulation. Mol Biol Cell 18:2569-78 |
| Mohlig, Heike; Mathieu, Sabine; Thon, Lutz et al. (2007) The WD repeat protein FAN regulates lysosome size independent from abnormal downregulation/membrane recruitment of protein kinase C. Exp Cell Res 313:2703-18 |
| Ward, Diane McVey; Vaughn, Michael B; Shiflett, Shelly L et al. (2005) The role of LIP5 and CHMP5 in multivesicular body formation and HIV-1 budding in mammalian cells. J Biol Chem 280:10548-55 |
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