Receptor mediated endocytosis in alveolar macrophages Alveolar macrophages play a major role in pulmonary homeostasis by clearing injurious agents from the lung. Macrophages remove these agents by internalizing them and directing them to lysosomes where they are sequestered and degraded. Macrophages also respond to their environment by secreting cytokines and other factors. Derangement of vesicular traffic results in the compromise of normal lung function. We will determine mechanisms involved in lysosome function, focusing on trafficking between the Multivesicular Body (MVB) and lysosome. Previously, we identified proteins required for the formation of the MVB. We will determine how the MVB delivers its contents to lysosomes and how lysosomal membranes are recycled. We cloned the gene responsible for the Chediak-Higashi Syndrome/beige. This autosomal recessive disease results in a phenotype that affects lysosomes, cytolytic granules, melanosomes, and platelet dense granules. We have determined functional domains of CHS/beige and using constructs expressing those domains, we will determine what functions of CHS/beige are required for lysosomal size regulation. We will use biochemical and proteomic approaches combined with our ability to isolate highly pure populations of lysosomes and endosomes at specific stages of maturation to determine proteins involved in endosome maturation and regulation of lysosome size. We discovered a protein, Mon1a, which is required for secretory vesicle traffic. A variant allele of this protein results in increased macrophage secretion of cytokines. We will determine the biochemical function of Mon1a and whether the variant allele is an inflammatory mediator in vivo.
. Alveolar macrophages play an essential role in maintaining lung function. Macrophages survey the environment removing hazardous particles including bacteria. Macrophages respond to the changing environment by secreting molecules that lead to inflammation. The ingestion of foreign particles and the secretion of molecules occur through the movement of vesicles within cells. Our studies on macrophage functions will provide information that may be used to manage and diagnose human diseases that affect vesicular trafficking and lung homeostasis.
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