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

 描述（由申请人提供）：我的长期职业目标是成为一名独立资助的，有成就的医生科学家，在预防儿童肾盂肾炎及其后遗症方面具有临床和研究专业知识。作为一名儿科肾病学家，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，这个K08指导临床科学家发展奖提案概述了一个计划，以促进在Kirk McHugh博士的指导下获得关键的研究和职业发展技能。大卫·海恩斯博士和谢里尔·贾斯蒂斯博士将提供额外的专业知识，我已经与他们建立了科学合作和生产力的记录。该研究咨询委员会将共同提供指导，以成功地从初级研究员过渡到独立资助的医生科学家。我将进一步受益于国家的最先进的设施和核心服务位于全国儿童医院和俄亥俄州州立大学。在我的培训期间，我将在实验室以及通过俄亥俄州州立大学的课堂教育获得新的实验和分析技能。我将培养口头和书面研究报告，科学合作，领导研究团队和研究人员的技能。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，并设计改进的诊断，预后和治疗方法，以照顾他们。我的短期职业目标是明确先天性梗阻性肾病（CON）患儿肾盂肾炎的发病机制。CON儿童特别容易患肾盂肾炎，这是该患者人群延长住院时间和进展为终末期肾病的独立风险因素。[1-3]我已经确定了显着的变化，基因表达，形态学和组成的肾尿路上皮细胞在小鼠模型的CON。[4]我推测CON扰乱了肾性尿路梗阻的结构和功能特性，使患者面临肾盂肾炎和肾瘢痕形成的风险。在具体目标1中，我将定义肾积水和肾性尿路梗阻结构完整性之间的关系。在具体目标2中，我将研究 CON对肾性尿路感染细菌结合和感染易感基因表达的影响。在具体目标3中，我将确定CON是否增加宿主对实验性肾盂肾炎和肾瘢痕形成的易感性。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发展基金会，以便在未来成功地竞争独立的R01资金。

 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.