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.

 说明(申请人提供)：抗菌肽(AMP)是免疫系统最原始的成分之一，也是自然界中使用最广泛的宿主防御分子类型。AMPS是一种基因编码的抗生素，由经常遇到参与宿主防御的微生物或细胞类型的细胞产生和分泌。在尿路中，AMP由膀胱、输尿管和肾小管的尿路上皮产生。我们已经确定核糖核酸酶7是一种高效的AMP，它表达在人的尿路中，保护尿路上皮免受泌尿系病原体的侵袭。我们发表的研究结果和初步数据表明，RNase7是一种理想的AMP候选药物，可作为一种新的尿路感染治疗药物。然而，虽然某些AMP在人类和低级脊椎动物之间是保守的，但小鼠基因组并不编码RNase7的同源基因。因此，我们对RNase7‘S在尿路宿主防御中的作用的了解是有限的。因此，这项建议的目标是开发创新的转基因小鼠模型，作为描述RNase7‘S相对大小和对动态平衡和宿主防御的特定贡献的有价值的工具。特殊目的1将创造一种新的小鼠模型，选择性地将人类RNase 7基因整合到小鼠基因组中。特定目标2将使用标准的Cre-loxP方法在小鼠尿路中全局和选择性地过表达RNASE7。利用这些模型，我们将评估RNase7过表达对发育中的小鼠尿路的影响。通过用新的和创新的小鼠模型研究核糖核酸酶7‘S的生物学影响，拟议的研究将对尿路上皮天然免疫产生独特的见解，并最终可能有助于开发像核糖核酸酶7这样的AMP，作为新的尿路感染治疗选择。