Developing MRI contrast agents to detect progression in renal disease as a consequence of acidema

开发 MRI 造影剂来检测酸血症导致的肾脏疾病的进展

基本信息

批准号：
10551303
负责人：
MICHAEL T MCMAHON
金额：
$ 39.57万
依托单位：
HUGO W. MOSER RES INST KENNEDY KRIEGER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10551303
关键词：
Acid-Base Equilibrium Age of Onset Biocompatible Materials Biological Markers Blood Blood Tests Blood Urea Nitrogen Body Weight decreased Buffers Chemicals Child Child Health Chronic Chronic Kidney Failure Clinical Coenzyme Q10 Collection Contrast Media Creatinine Detection Diagnostic Diet Dietary Supplementation Disease Drug Kinetics Early Diagnosis Electrodes Environment Evolution Filtration Fluorescein-5-isothiocyanate Frequencies Gadolinium Glomerular Filtration Rate Goals Health Histology Image Imidazole In Vitro Individual Injury to Kidney Inulin Ionizing radiation Kidney Kidney Diseases Kidney Failure LCN2 gene Magnetic Resonance Imaging Maps Measurement Measures Metabolic Diseases Methods Methylmalonyl-CoA Mutase Monitor Mus Mutase Mutation Nephrogenic Systemic Fibrosis New Agents Organ Patients Pentetic Acid Performance Perfusion Physiologic pulse Prediction of Response to Therapy Production Property Proteins Protocols documentation Protons Renal function Sampling Specificity Testing Tissues Transplantation Tubulointerstitial Nephritis Urinalysis Urine Vitamin E Weights and Measures amino acid metabolism design high risk imaging agent improved kidney biopsy methylmalonate methylmalonic aciduria mouse model organic acid perfusion imaging radiological imaging reduced muscle mass sensor sodium citrate

项目摘要

Organic acidemias are a class of inborn metabolic disorders which disrupt amino acid metabolism and lead to abnormal accumulation of organic acids detectable in blood, urine and other biomaterials. While individually rare, collectively these disorders have a significant impact on children’s health. Chronic Kidney Disease (CKD) is a cardinal feature of several organic acidemias, and patients require routine monitoring of kidney function to manage their treatment. Methylmalonic Acidemia (MMA) is an organic acidemia with a frequency of 1/50,000 to 1/100,000 caused by mutations in methylmalonyl-CoA mutase (Mut) with a predictable evolution to CKD. In fact, CKD is developed at a median onset age of 6.5 y in MMA patients who are at high risk of developing renal insufficiency. Unfortunately, current methods for monitoring renal health which include measuring blood creatinine and blood nitrogen urea are not reliable for MMA patients. An alternative strategy is to administer MRI contrast agents to acquire functional information on the kidneys. This proposal involves administering well tolerated, organic compounds which create MRI contrast through Chemical Exchange Saturation Transfer (CEST). An attractive feature of this mechanism is that it enables production of pH maps which reflect the environment surrounding the agents and might be particularly useful for the kidneys, organs which control the acid-base balance of the body. We will design CEST pH sensors which can monitor progression towards CKD through changes in pH and perfusion, and will provide a reliable indicator of the overall health of the kidneys. In Aim 1, we will synthesize a set of imidazole-4,5-dicarboxyamide probes to provide pH sensitive MRI contrast. The proton exchange rates and resulting CEST contrast will be quantified as a function of pH in buffered solutions to determine the performance of these in vitro. We will also optimize our pH and perfusion imaging protocol and characterize the pharmacokinetics using C57BL/6 control mice. In Aim 2, we will evaluate the sensitivity of our best agents from Aim 1 for detecting the extent of renal disease in the C57BL/6 Mut-/-;TgINS-Alb-Mut mouse model of MMA and validate the pH measurements using ISUCA. C57BL/6 Mut-/-;TgINS-Alb-Mut mice manifest chronic tubulointerstitial nephritis and a decreased glomerular filtration rate (GFR) which is initiated by placing the mice on a high protein (HP) diet for 2 months. In Aim 3, we will test our best sensor on six groups of mice with three groups treated with sodium citrate through diet supplementation and three more with CoQ10 + Vitamin E supplemented into their diets. The groups will also include three different timings for the high protein challenge which induces kidney injury. We expect our new agents and imaging protocols could provide an earlier detection of CKD without need of invasive kidney biopsy. This is particularly critical in conditions where standard monitoring methods are not feasible, such as MMA.

有机酸血症是一类先天性代谢紊乱，会破坏氨基酸代谢和导致血液、尿液和其他生物材料中可检测到的有机酸异常积累。这些疾病虽然个别罕见，但总的来说对儿童的健康有重大影响。疾病（CKD）是几种有机酸血症的主要特征，患者需要常规监测甲基丙二酸血症（MMA）是一种有机酸血症，具有以下特点：频率为 1/50,000 至 1/100,000 由甲基丙二酰辅酶 A 变位酶 (Mut) 突变引起 CKD 的可预测演变事实上，MMA 患者的 CKD 中位发病年龄为 6.5 岁。不幸的是，目前监测肾脏健康的方法存在肾功能不全的高风险。其中包括测量血肌酐和血氮尿素对于 MMA 患者来说并不可靠。另一种策略是使用 MRI 造影剂来获取肾脏的功能信息。建议涉及使用耐受性良好的有机化合物，通过以下方式产生 MRI 对比：该机制的一个吸引人的特点是它能够实现化学交换饱和转移。生成反映药剂周围环境的 pH 图，可能特别有用对于控制身体酸碱平衡的肾脏，我们将设计 CEST pH 传感器。它可以通过 pH 和灌注的变化监测 CKD 的进展，并提供可靠的肾脏整体健康状况的指标在目标 1 中，我们将合成一组咪唑-4,5-二羧酰胺。探针提供 pH 敏感的 MRI 对比度质子交换率和产生的 CEST 对比度将是我们还将根据缓冲溶液中的 pH 值进行定量，以确定其体外性能。优化我们的 pH 和灌注成像方案并使用 C57BL/6 对照表征药代动力学在目标 2 中，我们将评估目标 1 中的最佳药物用于检测肾损伤程度的敏感性。 MMA 的 C57BL/6 Mut-/-;TgINS-Alb-Mut 小鼠模型中的疾病，并使用以下方法验证 pH 测量 ISUCA. C57BL/6 Mut-/-;TgINS-Alb-Mut 小鼠表现出慢性肾小管间质性肾炎和肾小管间质性肾炎减少肾小球滤过率（GFR）是通过让小鼠接受高蛋白（HP）饮食两个月来启动的。在目标 3 中，我们将在六组小鼠上测试我们最好的传感器，其中三组接受柠檬酸钠治疗通过饮食补充，还有另外三个人在饮食中添加了辅酶 Q10 + 维生素 E。小组还将包括三种不同时间的高蛋白挑战，这会导致肾损伤。预计我们的新药物和成像方案可以提供 CKD 的早期检测，而无需这在没有标准监测方法的情况下尤其重要。可能的，比如MMA。