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

描述(申请人提供)：现有的早期肾脏疾病的临床标记物非常有限。更好地监测和管理肾脏疾病是一个迫切的、尚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)磁共振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导师研究科学家发展奖(K01)的申请还包括Cornelius von Morze博士的导师职业发展计划，以实现他作为独立研究员的最终职业目标。这一重新提交的申请包含增强的多学科研究和培训计划，以改善科学和临床影响。冯·莫尔兹博士将研究基于新型超极化(HP)13C磁共振分子成像造影剂的新造影剂机制，以探索临床前模型中关键的肾脏运输和代谢过程。HP尿素显像剂与参比示踪剂共偏振并同时成像，将用于探测高特异性的肾脏尿素转运。惠普尿素成像将用于监测尿素转运的临床显著改变状态：与非类固醇抗炎药使用相关的进行性肾损害，以及新型“尿毒症”药物诱导的利尿。HP乳酸的分子成像将被作为肾脏糖异生的一种新的探针进行研究，它是空腹状态下血糖平衡的关键因素，而空腹状态下2型糖尿病患者的血糖水平显著且选择性地失调。这些成像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，并具有临床转译的潜力。Cornelius von Morze博士的研究生工作专注于先进的MRI技术开发，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开发和应用，特别是在肾脏成像方面。这项建议中描述的有指导的职业发展计划将扩大冯·莫尔茨博士的知识面，拥有临床前模型、肾脏生理学、生物分析和组织学方面的理论和实验经验。他还将提高自己在假设驱动的研究和实验室管理方面的技能。NIDDK K01项目旨在实现他的长期目标，即引领世界一流的独立大学在肾脏疾病磁共振分子成像方面的研究，用于实验性疾病模型和最终患者的研究，以满足目前尚未得到满足的临床需求。

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.