ALTRUINS, NATURAL ANTIBIOTICS OF THE MALE GENITAL TRACT

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Long term objectives. To discover the endogenous antimicrobial effector molecules of humans, and to define their structures and mechanisms of action. This proposal deals with antimicrobial peptides of the male genital tract, an area where remarkably little information currently exists. Hypotheses. Normal human semen contains proteins with latent antimicrobial domains that are activated by serine and aspartyl proteases found in normal semen. The resulting peptides ("altruins") can protect the female from infection by bacteria introduced into the vagina during intercourse. Specific aims. 1). To identify and characterize antimicrobial peptides and their precursors in human semen. 2). To ascertain how the precursors of these peptides are processed and identify the responsible proteases. 3). To test these peptides against C. trachomatis, E. coli, STD pathogens, and normal vaginal flora. 4). To synthesize selected seminal peptides, and elucidate their mechanisms of action. Methods. We will apply various purification procedures, including gel permeation chromatography, preparative electrophoresis and RP-HPLC to purify the antimicrobial components of normal and pH conditioned semen. These fractions will be tested for antimicrobial activity, and the active effector molecules they contain will be purified to homogeneity, sequenced, synthesized, and studied. Health relatedness. Many of the most common infectious diseases in the U.S. are sexually transmitted. According to CDC estimates, STDs other than AIDS add 10 billion dollars to the nation's annual health care I costs. The proposed studies could lead to novel approaches for STD prophylaxis.