I intend to devote the next phase of my research career to learning new approaches to study the pulmonary alveolar macrophage (PAM). As a pulmonary physician, I am keenly aware of the lack of fundamental understanding of many acute lung diseases, such as fungal lung infections in AIDS patients, and chronic lung diseases, including sarcoidosis and pulmonary fibrosis; the study of the PAM, the cellular arm of the lung's first line of defense, will yield essential insights into acute and chronic inflammatory diseases. Fundamental questions about two types of cell surface receptors that are present on PAM, the mannose receptor and Fc receptorswill be addressed. Both are competent for multiple functions, including endocytosis and phagocytosis, and endow the PAM with the means of clearing fungal agents, via the mannose receptor, and a multitude of pathogens that elicit a humoral immune response, via Fc receptors. In addition, Fc receptors may have a broader function in immunity, including the clearance of immune complexes and the destruction of tumors. I will create and characterize a particle capable of being recognized and ingested by the mannose receptor of PAMs and related cell lines, such as J774 cells. I will select J774 cells which lack mannose receptors and transfect into them cloned mannose receptors and various mannose receptor mutants. This will allow me to study the structural requirements for phagocytosis, endocytosis, and relevant aspects of signal transduction, including actin polymerization. By constructing and transfecting chimeric mannose/Fc receptors I will answer essential questions concerning signal transduction of both receptors. Finally, I will explore the mechanisms by which these receptors communicate with the cytoskeleton, and study the sole of contractile and related proteins, including F-actin and talin, in receptor-mediated phagocytosis.
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