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

项目摘要/摘要 现有的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 疾病是一种迫切的、未得到满足的医疗需求。该项目的总体目标是开发新的应用程序 超极化碳-13(13C)磁共振技术用于监测肾脏疾病。除了候选人的 研究计划，本申请NIDDK导师研究科学家发展奖(K01)还 包括科尼利厄斯·冯·莫泽博士的职业发展指导计划，以实现他的终极职业目标 作为一名独立调查员。这份重新提交的申请包含了增强的多学科研究 和培训计划，以提高科学和临床影响。 冯·莫尔兹博士将研究基于新型超极化(HP)13C磁共振的新造影剂机制 分子成像造影剂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，共偏振，并与参考示踪剂同时成像，将应用于探头 肾尿素转运具有较高的特异性。HP尿素成像将用于监测临床上有意义的改变 尿素转运状态：与非甾体抗炎药使用相关的进行性肾损害，以及新型“尿失禁”药物- 诱导利尿。幽门螺杆菌乳酸作为一种新型肾脏探针的分子成像研究 糖异生是空腹状态下血糖稳态的关键因素，而禁食状态下的葡萄糖代谢 2型糖尿病患者的选择性调节失调。这些成像研究将使高度新颖的 临床前小鼠模型中肾脏疾病的特征。这项研究旨在改善监测和 由于非侵入性、安全性和安全性，肾脏疾病的治疗具有临床转归的潜力 这些新的分子磁共振成像方法的可行性。 科尼利厄斯·冯·莫泽博士的研究生工作重点是先进的核磁共振技术开发和他的 博士后研究导致了新型HP 13C磁共振的新技术开发和应用 分子成像造影剂，特别是肾脏成像。辅导式职业发展计划 这项提案中描述的内容将通过理论和实验扩展冯·莫尔茨博士的知识广度 具有临床前模型、肾脏生理学、生物检验和组织学方面的经验。他还将提高他的 以假设为导向的研究和实验室管理技能。这个NIDDK K01项目已经 旨在实现他领导世界一流独立大学MR分子研究的长期目标 肾脏疾病的成像研究既是实验性疾病模型，也是最终患者要解决的问题 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.