The human neutrophil is an essential cellular component of host defense against infection and plays and important role in the acute inflammatory response. For both of these functions, a prominent cellular event is the fusion of lysosomes with the plasma membrane. This process is involved in the microbicidal activity of these cells during phagosome-lysosome fusion and in the release of hydrolytic lysosomal enzymes important to the evolution of acute inflammation. Membrane fusion is also fundamental to such diverse biologic processes as egg fertilization by spermatozoa, neurotransmittor release from synaptic vesicles and secretion of a wide variety of essential hormones, digestive enzymes and vasoactive amines. This proposal outlines and integrated study of the anatomy and regulation of fusion between neutrophil lysosomes and the plasma membrane. Particular areas of focus will be on the location and function of translocated lysosomal membrane constituents in the plasma membrane, the role of an intralysosomal acidic pH in regulating the fusion process, the mechanisms which maintain the intralysosomal and intracellular pH and modifications of membrane proteins which are coincident with membrane fusion. We will extend preliminary studies which indicate that alkalinizing the intralysosomal pH inhibits lysosome-plasma membrane fusion and that a novel class of membrane proteins (proteolipids) are present in membranes of normal neutrophils and undergo modification when cells are stimulated to secrete. Studies on normal neutrophils will be used as a framework to study the disordered membrane fusion which occurs in the Chediak-Higashi syndrome of cats and humans.
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