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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代谢紊乱，它会破坏氨基酸的代谢