This proposal is a continuation of a highly successful program of characterization of a family of human host defense peptides, defensins. Accumulated evidence from studies in humans, as well as in animals and plants, strongly supports the important role of defensins in innate immunity. Most defensins at physiologic concentrations are antimicrobial and some defensins also have chemokine-like activities. In previous studies we characterized the abundant defensins from polymorphonuclear leukocytes but more recently we focused on other defensin peptides expressed in resting and inflamed epithelia. We will now examine the biology of the inflammation and infection-inducible epithelial human beta-defensin-2, and characterize the biologically-related human beta-defensin-3. Continuing with our studies of human neutrophil defensins, we will identify and characterize the prodefensin convertase, a key enzyme for the activation of neutrophil defensins and an attractive target for experimental ablation of defensin activity. We will: 1) Characterize the synthesis, cellular and subcellular distribution, and biological function of the inducible epithelial defensin HBD2; 2) Analyze the regulation of HBD2 response in organotypic epidermal culture and in a transgenic reporter mouse; 3) Biosynthesize the newly discovered beta-defensin HBD3 and characterize its bioactivities, its tissue distribution and its inducibility by infectious and inflammatory stimuli; 4) Identify and characterize the neutrophil defensin convertase, the enzyme responsible for defensin activation. In the aggregate, these studies will expand our understanding of is ubiquitous and multifunctional family of human host defense peptides, this time also in their role as effectors of innate immunity in epithelia.
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