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

项目总结/摘要 早期肾脏疾病的现有临床标志物非常有限。更好地监测和管理肾脏疾病 疾病是一个迫切的未满足的医疗需求。该项目的总体目标是开发新的 超极化碳-13（13 C）MRI技术用于监测肾脏疾病。除了候选人的 研究计划，这一申请NIDDK指导研究科学家发展奖（K 01）还 包括科尼利厄斯·冯·莫尔斯博士的指导职业发展计划，以实现他的最终职业目标 作为一名独立调查员此重新提交的应用程序包含增强的多学科研究 和培训计划，以提高科学和临床的影响。 博士von Morze将研究基于新型超极化（HP）13 C MR的新对比机制 分子成像造影剂，用于在临床前模型中探测关键的肾脏转运和代谢过程。 HP尿素成像，与参考示踪剂共极化并同时成像，将应用于探头 肾脏尿素转运具有高度特异性。HP尿素成像将用于监测临床显著改变 尿素转运状态：与NSAID使用相关的进行性肾损伤，以及新型“利尿”药物- 诱导利尿。HP乳酸的分子成像将作为肾脏疾病的一种新的探针进行研究 葡萄糖生成是空腹状态下葡萄糖稳态的关键因素， 2型糖尿病的选择性失调。这些影像学研究将允许高度新颖的 临床前鼠模型中肾脏疾病的表征。这项研究旨在改善监测和 肾脏疾病的管理，由于其无创性、安全性和 这些新的分子MR成像方法的可行性。 博士Cornelius von Morze的研究生工作主要集中在先进的MRI技术开发上， 博士后研究导致了新的技术开发和新的HP 13 C MR的应用 分子成像造影剂，特别是用于肾成像的造影剂。指导职业发展计划 本提案中所描述的技术将扩大冯·莫尔斯博士的理论和实验知识广度， 在临床前模型、肾脏生理学、生物测定和组织学方面的经验。他还将提高他的 假设驱动的研究和实验室管理的技能。该NIDDK K 01项目已被 旨在使他的长期目标，领先世界一流的独立大学研究的MR分子 肾脏疾病的影像学研究既针对实验性疾病模型，又最终针对患者 目前尚未满足的临床需求。

PROJECT SUMMARY / ABSTRACT 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.