Ribonuclease 7: Antimicrobial Activity in the Human Kidney and Urinary Tract

应聘者描述(由申请人提供)：应聘者的长期目标是成为一名在儿科肾病学术领域有成就的独立内科医生和科学家，在诊断、治疗和预防尿路感染(UTI)方面具有临床和研究专长。这份由导师指导的K08职业发展奖提案概述了一项计划，候选人将在拥有成功合作记录的导师和合作者团队的指导下进行培训。这个研究顾问团队在指导学员和初级教员作为独立的内科科学家取得成功的职业生涯方面拥有广泛的经验和成功。候选人将受益于最先进的设施和来自临床、基础和一般核心服务的广泛支持。他将从以下方面获得新的研究和分析技能 实践指导的实验室指导和俄亥俄州立大学的课堂教育。他将在口头和书面科学交流、学术团队领导和合作以及格兰特精神方面建立一套能力。拟议研究项目的长期目标是通过确定有效的早期生物标记物和新的治疗方案来诊断和治疗尿路感染，从而改善儿童尿路感染患者的护理。这项拟议的研究项目将检验这样一种假设，即抗菌肽(AMP)是先天性免疫系统中普遍存在的成分，在调节和预防尿路感染方面很重要。这项拟议的研究将确定一种新的AMP，核糖核酸酶7(RNase7)的功能，它最近被证明具有强大的抗菌特性，并在维持尿路无菌方面发挥重要作用。这项工作的预期结果是促进我们对RNase7在尿路感染预防和治疗中的作用的理解，并确定该蛋白在尿路感染诊断和治疗中的潜在用途。具体目的1旨在表征RNase7在健康和感染状态下的抗微生物特性。特殊目的2旨在通过鉴定负责其抗菌功能的关键氨基酸残基，在结构和功能水平上表征RNase7。特异靶3旨在评估RNASE 7中单核苷酸多态的频率和生物学相关性。成功完成这些拟议的目标和教育计划将有助于开发所需的专业知识，以系统地评估人类尿路中的AMP，如RNase7。 公共卫生相关性：尿路感染是医生遇到的最常见和最严重的细菌感染之一。没有一种治疗策略被证明在预防UTI后遗症方面是有效的，而且泌尿系病原菌的抗生素耐药性正在增加。抗菌肽(AMP)是天然免疫系统的一个组成部分，是一类很有前途的新型潜在抗生素，可以克服传统疗法的局限性和出现的细菌耐药性问题。在这项研究中，我们将评估核糖核酸酶7的结构、功能和生物学相关性，核糖核酸酶7是一种新型的AMP，在人类尿路中具有强大的抗菌特性。

DESCRIPTION (provided by applicant): The candidate's long-term goal is to become an accomplished independent physician-scientist in academic pediatric nephrology with clinical and research expertise in the diagnosis, treatment, and prevention of urinary tract infections (UTI). This mentored K08 Career Development Award proposal outlines a plan where the candidate will train under the guidance of a team of mentors and collaborators that have a successful track record of working together. This Research Advisory Team has extensive experience and success in guiding trainees and junior faculty to successful careers as independent physician-scientists. The candidate will benefit from state-of-the-art facilities and extensive support from clinical, basic, and general core services. He will acquire new research and analytical skills from hands-on directed laboratory mentorship and a classroom- based education at The Ohio State University. He will build a repertoire of competencies in oral and written scientific communication; academic team leadership and collaboration; and grantsmanship. The long-term objectives of the proposed research project are to improve the care of pediatric patients with UTIs by identifying effective early biomarkers and novel treatment options for the diagnosis and treatment of UTIs. The proposed research project will test the hypothesis that antimicrobial peptides (AMP), a ubiquitous component of the innate immune system, are important in the regulation and prevention of UTIs. The proposed research will define the function of a novel AMP, ribonuclease 7 (RNase 7), which has recently been shown to have potent antimicrobial properties and play an important role in maintaining urinary tract sterility. The anticipated outcome of this work is advancement of our understanding of the role of RNase 7 in the prevention and treatment of UTIs and to identify the potential use of this protein in UTI diagnostics and therapeutics. Specific Aim 1 is designed to characterize the antimicrobial properties of RNase 7 in states of health and infection. Specific Aim 2 is designed to characterize RNase 7 at the structural and functional level by identifying critical amino acid residues that are responsible for its antimicrobial function. Specific Aim 3 is designed to evaluate the frequency and biological relevance of single nucleotide polymorphisms in RNASE7. Successful completion of these proposed aims and educational plan will help develop the needed expertise to systematically evaluate AMPs, like RNase 7, in the human urinary tract. PUBLIC HEALTH RELEVANCE: Urinary tract infections are one of the most common and serious bacterial infections encountered by physicians. No treatment strategy has proven to be effective in the prevention of UTI sequelae, and antibiotic resistance is increasing in uropathogenic bacteria. Antimicrobial peptides (AMP), a component of the innate immune system, are a promising new class of potential antibiotics that may overcome the limitations of traditional therapies and the emerging problems of bacterial resistance. In this study, we will evaluate the structure, function, and biological relevance of ribonuclease 7, a novel AMP that has potent antimicrobial properties in the human urinary tract.