Molecular Imaging of Renal Transport and Metabolism using Hyperpolarized C-13 MRI

描述（由申请人提供）：现有早期肾脏疾病的临床标志物非常有限。更好地监测和管理肾脏疾病是一项迫切的未得到满足的医疗需求。该项目的总体目标是开发新的超极化碳-13 (13C) MRI技术在肾脏疾病监测中的应用。除了候选人的研究计划外，NIDDK指导研究科学家发展奖（K01）的申请还包括指导Cornelius von Morze博士的职业发展计划，以实现他作为独立研究者的最终职业目标。此重新提交的申请包含增强的多学科研究和培训计划，以提高科学和临床影响。von Morze博士将研究基于新型超极化（HP） 13C MR分子成像造影剂的新型造影剂机制，以在临床前模型中探测关键的肾脏运输和代谢过程。HP尿素成像，共极化和与参考示踪剂同时成像，将用于高特异性地探测肾脏尿素运输。HP尿素显像将用于监测尿素转运的临床显著改变状态：与使用非甾体抗炎药相关的进行性肾损害，以及新型“尿毒症”药物引起的利尿。HP乳酸的分子成像将作为肾脏糖异生的一种新探针进行研究，糖异生是2型糖尿病患者空腹状态下葡萄糖稳态的关键因素。这些影像学研究将允许在临床前小鼠模型中对肾脏疾病进行高度新颖的表征。由于这些新的分子磁共振成像方法的无创性、安全性和可行性，本研究旨在改善肾脏疾病的监测和管理，并具有临床转化的潜力。Cornelius von Morze博士的研究生工作重点是先进的MRI技术发展，他的博士后研究导致了新型HP 13C MR分子成像造影剂的新技术发展和应用，特别是用于肾脏成像。本提案中描述的指导职业发展计划将通过临床前模型，肾脏生理学，生物分析和组织学方面的理论和实验经验扩展von Morze博士的知识广度。他还将提高他在假设驱动研究和实验室管理方面的技能。该NIDDK K01项目旨在实现他的长期目标，即领导世界级独立大学在肾脏疾病MR分子成像方面的研究，以研究实验性疾病模型和最终患者，以解决目前未满足的临床需求。

DESCRIPTION (provided by applicant): Existing clinical markers for early renal disease are very limited. Better monitoring and management of renal disease is a pressing unmet medical need. The overall goal of this project is to develop the application of new hyperpolarized carbon-13 (13C) MRI technology for monitoring renal disease. In addition to the candidate's research plan, this application for a NIDDK Mentored Research Scientist Development Award (K01) also includes a mentored career development plan for Dr. Cornelius von Morze to achieve his ultimate career goals as an independent investigator. This resubmission application contains enhanced multi-disciplinary research and training plans for improved scientific and clinical impact. Dr. von Morze will investigate new contrast mechanisms based on novel hyperpolarized (HP) 13C MR molecular imaging contrast agents to probe key renal transport and metabolic processes in preclinical models. HP urea imaging, co-polarized and imaged simultaneously with a reference tracer, will be applied to probe renal urea transport with high specificity. HP urea imaging will be applied to monitor clinically significant altered states of urea transport: progressive renal damage associated with NSAID use, and novel "urearetic" drug- induced diuresis. Molecular imaging of HP lactic acid will be investigated as a novel probe of renal gluconeogenesis, a crucial contributor to glucose homeostasis in the fasting state which is dramatically and selectively dysregulated in type 2 diabetes mellitus. These imaging studies will allow highly novel characterization of renal disease in preclinical murine models. This research aims to improve monitoring and management of renal disease with the potential for clinical translation due to the noninvasiveness, safety, and feasibility of these new molecular MR imaging methods. Dr. Cornelius von Morze's graduate work focused on advanced MRI technique development and his postdoctoral research has resulted in new technical development and applications of novel HP 13C MR molecular imaging contrast agents, particularly for renal imaging. The mentored career development plan described in this proposal will expand Dr. von Morze's breadth of knowledge with theoretical and experimental experience in preclinical models, renal physiology, biological assays and histology. He will also improve his skills for hypothesis-driven research and in laboratory management. This NIDDK K01 project has been designed to enable his long-term goal of leading world-class independent university research in MR molecular imaging of renal disease for the study of both experimental disease models and ultimately patients to address currently unmet clinical needs.