Role of urothelium in epithelial integrity and innate defense of the kidney

尿路上皮在上皮完整性和肾脏先天防御中的作用

• 批准号: 9497794
• 负责人: Brian Becknell
• 金额: $ 15.36万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9497794
• 关键词: Acute; Advisory Committees; Animals; Bacteria; Bacterial Attachment Site; Binding; Career Mobility; Caring; Cell Membrane Permeability; Child; Child Care; Childhood; Chronic; Chronic Kidney Failure; Clinical; Clinical Research; Collaborations; Complication; Deterioration; Diagnostic; Education; End stage renal failure; Epithelial; Exhibits; Familiarity; Fibrosis; Foundations; Funding; Future; Gene Expression; Gene Proteins; Goals; Hospitalization; Hydronephrosis; Impairment; Infection; Inflammation; Innate Immune Response; Intervention; Justice; Kidney; Kidney Diseases; Laboratories; Lead; Leadership; Measures; Mentored Clinical Scientist Development Award (K08); Mentors; Mentorship; Modeling; Morbidity - disease rate; Morphology; Mus; Natural Immunity; Obstruction; Ohio; Operative Surgical Procedures; Oral; Pathogenesis; Pathogenicity; Patients; Pediatric Hospitals; Permeability; Physicians; Play; Predisposition; Prevention; Productivity; Property; Pyelonephritis; Recurrence; Renal function; Research; Research Personnel; Risk; Risk Factors; Role; Scientist; Services; Structural Protein; Structure; Susceptibility Gene; Testing; Therapeutic; Training; Universities; Urinary tract; Urinary tract infection; Urine; Urothelium; Work; base; career; education planning; experience; improved; insight; modifiable risk; mouse model; patient population; prevent; prognostic; public health relevance; renal abscess; renal scarring; skills; theories; treatment strategy; urinary tract obstruction

 DESCRIPTION (provided by applicant): My long-term career objective is to become an independently funded, accomplished physician-scientist with clinical and research expertise in the prevention of pyelonephritis and its sequelae in children. As a pediatric nephrologist, I aim t leverage clinical and scientific training to prevent deterioration of kidney function in these patients. To accomplish these objectives, this K08 Mentored Clinical Scientist Development Award proposal outlines a plan to facilitate the acquisition of key research and career advancement skills under the mentorship of Dr. Kirk McHugh. Additional expertise will be provided by Drs. David Hains and Sheryl Justice, two investigators with whom I already have an established record of scientific collaboration and productivity. Together, this Research Advisory Committee will provide guidance to successfully transition from a junior investigator to an independently funded physician-scientist. I will benefit further from state-of-the-art facilities ad core services located at Nationwide Children's Hospital and The Ohio State University. During my training, I will acquire new experimental and analytical skills in the laboratory as well as through classroom- based education at The Ohio State University. I will develop skills in oral and written presentation of research, scientific collaboration, leadership of a research team, and grantsmanship. The long-term research objectives of this work are to elucidate the pathogenic mechanisms of pyelonephritis and its sequelae in children, and to devise improved diagnostic, prognostic and therapeutic approaches to their care. My short-term career goal is to define the pathogenesis of pyelonephritis in children with congenital obstructive nephropathy (CON). Children with CON are especially vulnerable to pyelonephritis, which is an independent risk factor for prolonged hospitalization and progression to end-stage renal disease in this patient population.[1-3] I have identified significant changes in gene expression, morphology, and composition of renal urothelium in a murine model of CON.[4] I hypothesize that CON perturbs structural and functional properties of renal urothelium, placing patients at risk for pyelonephrits and renal scarring. In Specific Aim 1, I will define the relationship between hydronephrosis and structural integrity of renal urothelium. In Specific Aim 2, I will investigate the consequences of CON on bacterial binding and the expression of infection susceptibility genes by renal urothelium. In Specific Aim 3, I will determine if CON increases host susceptibility to experimental pyelonephritis and renal scarring. Completion of these research aims and the training proposed in my educational plan will allow me to develop the foundation to successfully compete for independent R01 funding in the future.

 个人描述(申请人提供)：我的长期职业目标是成为一名独立资助、成就卓著的内科科学家，在预防儿童肾盂肾炎及其后遗症方面具有临床和研究专长。作为一名儿科肾科医生，我的目标是利用临床和科学培训来防止这些患者的肾功能恶化。为了实现这些目标，这份K08临床科学家导师发展奖提案概述了一项计划，以促进在柯克·麦克休博士的指导下获得关键的研究和职业发展技能。大卫·海恩斯博士和谢丽尔·贾斯蒂斯博士将提供更多的专业知识，这两位研究人员已经与我建立了科学合作和生产力的记录。这个研究咨询委员会将共同为成功地从初级研究员过渡到独立资助的内科科学家提供指导。我将进一步受益于位于全国儿童医院和俄亥俄州立大学的最先进的设施和核心服务。在我的培训期间，我将在实验室以及俄亥俄州立大学的课堂教育中获得新的实验和分析技能。我将发展研究的口头和书面陈述、科学合作、研究团队的领导能力和大方精神。这项工作的长期研究目标是阐明儿童肾盂肾炎及其后遗症的发病机制，并设计出改进的诊断、预后和治疗方法。我的短期职业目标是明确先天性梗阻性肾病(CON)儿童肾盂肾炎的发病机制。患有CON的儿童特别容易患肾盂肾炎，这是该患者群体中延长住院时间和进展为终末期肾脏疾病的独立危险因素。[1-3]我在CON的小鼠模型中发现了肾脏尿路上皮基因表达、形态和成分的显著变化。[4]我假设CON扰乱了肾脏尿路上皮的结构和功能特性，使患者面临肾结石和肾疤痕形成的风险。在具体目标1中，我将明确肾积水与尿路上皮结构完整性之间的关系。在具体目标2中，我将调查 尿路上皮细菌结合与感染易感基因表达的关系在具体目标3中，我将确定CON是否会增加宿主对实验性肾盂肾炎和肾疤痕形成的易感性。完成这些研究目标和我的教育计划中提出的培训将使我能够为未来成功竞争独立的R01资金奠定基础。