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

评估核糖核酸酶 7 在尿路防御中体内意义的新型小鼠模型

• 批准号: 9091881
• 负责人: John David Spencer
• 金额: $ 7.99万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9091881
• 关键词: Acute; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Infections; Biological; Bladder Urothelium; Cells; Data; Foundations; Genes; Genomics; Health; Homeostasis; Host Defense; Human; Immune; Immune response; Immune system; Intercalated Cell; Kidney; Knowledge; Microbe; Modeling; Morbidity - disease rate; Mus; Natural Immunity; Nature; Orthologous Gene; Patient Care; Physicians; Positioning Attribute; Prevention; Publishing; Pyelonephritis; Renal tubule structure; Research; Ribonucleases; Role; Stream; Therapeutic; Toxic effect; Transgenic Mice; Ureter; Urinary tract; Urinary tract infection; Uropathogen; Urothelium; Vertebrates; antimicrobial; antimicrobial peptide; bacterial resistance; cell type; improved; in vivo; inducible gene expression; innovation; insight; microbial; mortality; mouse genome; mouse model; novel; novel therapeutics; overexpression; prevent; public health relevance; recombinase; tool; traditional therapy; treatment strategy; urinary

 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.