The mechanism of cell adhesion takes on special significance in studies of the immune response due to the unique nature of the primary constituents of the response, circulating cells. Most organ systems are comprised of cells whose position within the tissue of fixed during differentiation. Alternatively, the immune organ system consists of cell types that are continually being derived de novo from bone marrow precursors and must seek out selected sites within the body for their specific functions. The mammalian mast cell represents a cell which, like many of its lymphocyte counterparts, occupies specific sites within the animal. Thus the connective tissue mast cell selectively resides within the skin, muscle and peritoneal cavity, and the mucosal mast cell is primarily found within the submucosa, lamina propria and intraepithelial space of the gastrointestinal and respiratory tracts. We have isolated a novel gene, dubbed Pactolus, that is related to the family of beta integrins. The gene is selectively expressed in maturing connective tissue mast cells compared to mucosal mast cells. The tissue of the animal that displays the highest level of expression is the bone marrow. This application proposes to define the function of the Pactolus protein within the mouse by developing a series of immunologic and nucleic acid-based reagents to study its expression, association with other proteins, its function as a ligand-specific adhesion receptor, and its possible role as a connective tissue homing receptor for maturing connective tissue mast cells. Studies are proposed to isolate the human counterpart and to determine the human and murine gene locations in the genome. The generation of mouse strains that lack functional Pactolus via the knockout of the normal gene is also proposed. Finally the expression pattern of Pactolus suggests its transcription is controlled, in part, by a c-kit signal transduction pathway. We propose to analyze this control pathway, identifying regions of the Pactolus gene that are critical for transcriptional induction and identifying the proteins that effect this control. By following this experimental regime, the role of murine Pactolus in the immune response of the animal will be elucidated. These data will provide the key information needed to establish similar investigations into the role and functions of human Pactolus.
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