Novel Mouse Models to Assess the in vivo Significance of Ribonuclease 7 in Urinary Tract Defense

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 DESCRIPTION (provided by applicant): Antimicrobial peptides (AMPs) are one of the most primitive components of the immune system and are arguably the most widely used type of host defense molecule in nature. AMPs are gene-encoded antibiotics that are produced and secreted by cells that routinely encounter microbes or cell types that are involved in host defense. In the urinary tract, AMPs are produced by the urothelium of the bladder, ureter, and the renal tubules. We have identified Ribonuclease 7 as a potent AMP expressed the human urinary tract that shields the urothelium from uropathogenic bacteria. Our published findings and preliminary data suggest that RNase 7 is an ideal candidate AMP to develop as a novel UTI therapeutic. However, while certain AMPs are conserved between humans and lower order vertebrates, the mouse genome does not encode an ortholog of RNase 7. As a result, our understanding of RNase 7's role in urinary tract host defense is limited. Thus, the objective for this proposal is t develop innovative new transgenic mouse models that will serve as valuable tools to delineate RNase 7's relative magnitude and specific contributions to homeostasis and host defense. Specific Aim 1 will create a novel mouse model that selectively integrates the human RNASE7 gene into the mouse genome. Specific Aim 2 will use a standard Cre-loxP approach to globally and selectively overexpress RNASE7 in the murine urinary tract. Using these models, we will evaluate the impact of RNase 7 overexpression on the developing murine urinary tract. By studying RNase 7's biological impact with new and innovative mouse models, the proposed research will generate unique insights into urothelial innate immunity and ultimately may help develop AMPs, like RNase 7, as new UTI treatment options.