Metabolic imaging of hyperpolarized 13C pyruvate in polycystic kidney disease

多囊肾病中超极化 13C 丙酮酸的代谢成像

基本信息

批准号：
10527162
负责人：
Dirk Mayer
金额：
$ 11.77万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10527162
关键词：
Address Adult Affect Animal Cancer Model Animal Model Animals Autosomal Dominant Polycystic Kidney Biological Assay Cells Citric Acid Cycle Clinical Clinical Research Cyst Cystic kidney Data Deoxyglucose Development Dimensions Disease Disease Progression End stage renal failure Energy Metabolism Evaluation Female Functional disorder Genes Glycolysis Goals Growth Harvest Human Hypertension Image Imaging Device In Vitro Individual Inherited Kidney Kidney Diseases Knowledge Label Link Longitudinal Studies Magnetic Resonance Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Malignant neoplasm of brain Malignant neoplasm of prostate Measurement Measures Metabolic Metabolic Pathway Metabolism Metformin Methods Mus National Institute of Diabetes and Digestive and Kidney Diseases Noise Nuclear Patient Care Patient-Focused Outcomes Patients Pharmaceutical Preparations Play Polycystic Kidney Diseases Process Pyruvate Pyruvate Metabolism Pathway Reaction Research Role Scheme Sex Differences Signal Transduction Techniques Time Tissues Translating Transport Process Vasopressins Warburg Effect base computerized data processing denoising early onset enzyme activity experimental group imaging modality improved improved outcome in vitro Assay in vivo interest kidney metabolism male malignant breast neoplasm metabolic imaging mitochondrial metabolism mouse model neoplastic cell new technology new therapeutic target non-invasive imaging novel personalized medicine pre-clinical research preclinical study prevent real-time images receptor response spectroscopic imaging technology development tolvaptan tool tool development tumor

项目摘要

In response to NIDDK’s NOSI NOT-DK-20-034 “Advancing Polycystic Kidney Disease (PKD) Research through Catalytic Tool and Technology Development”, the overarching goal of this proposal is to develop new metabolic imaging tools for investigating the metabolic alterations in PKD. Autosomal dominant PKD (ADPKD) is the most common inherited renal disease and is estimated to affect 1/2500 to 1/1000 individuals worldwide. However, there is currently no cure and additional therapies that will completely delay or prevent renal cyst formation are still an unmet clinical need. Recently there has been increased interest in aspects of altered metabolism in cystic cells with multiple lines of evidence suggesting that metabolic reprogramming is an intrinsic component of the disease. Better understanding the relation between metabolic dysregulation and cystogenesis could aid in identifying new therapeutic targets. One important discovery was the fact that the deletion of a ADPKD gene, PKD1, upregulates the rate of glycolysis in a manner similar to the Warburg effect in tumor cells. However, a current limitation of the methods investigating metabolic processes in ADPKD is that they do not measure cellular metabolism in the normal microenvironment as they rely on in vitro assays. The recent development of hyperpolarized (HP) 13C MR spectroscopy (MRS) enables for the first time the real-time noninvasive measurement of critical dynamic metabolic processes in vivo. So far, the most widely used substrate is [1-13C]pyruvate (Pyr) and it has been shown in both preclinical and clinical studies that its conversion to lactate (Lac) is sensitive to the high glycolytic rates in tumors. Therefore, we propose first to develop a HP 13C MRS-based approach for noninvasively assessing the metabolic reprogramming in ADPKD. Specifically, we will develop optimized MR acquisition and quantification techniques for improved metabolic imaging of both HP [1-13C] and [2-13C]Pyr and their respective metabolic products enabling the simultaneous measurement of both glycolytic and mitochondrial metabolism (Aim 1). Secondly, we will evaluate these techniques in their ability to detect altered kidney metabolism in a longitudinal study in a murine model of ADPKD (Aim 2). If successful, metabolic imaging of HP Pyr would represent a critical advance for both preclinical and clinical research of ADPKD and could add to the toolbox of personalized medicine for patient care.

响应 NIDDK 的 NOSI NOT-DK-20-034“推进多囊肾病 (PKD) 研究通过催化工具和技术开发”，该提案的总体目标是开发新的用于研究常染色体显性 PKD (ADPKD) 代谢改变的代谢成像工具。是最常见的遗传性肾脏疾病，估计影响全世界 1/2500 至 1/1000 人。然而，目前没有治愈方法和其他疗法可以完全延迟或预防肾囊肿形成仍然是一个未满足的临床需求，最近人们对这些方面的兴趣日益增加。囊性细胞中的代谢有多种证据表明代谢重编程是一种更好地了解代谢失调与疾病之间的关系。细胞发生可以帮助确定新的治疗靶点。 ADPKD 基因 PKD1 的缺失会以类似于 Warburg 效应的方式上调糖酵解速率然而，目前研究 ADPKD 代谢过程的方法的局限性是它们不测量正常微环境中的细胞代谢，因为它们依赖于体外测定。最近开发的超极化 (HP) 13C 磁共振波谱 (MRS) 首次实现了实时迄今为止应用最广泛的体内关键动态代谢过程的无创测量。底物是[1-13C]丙酮酸（Pyr），临床前和临床研究均表明其转化为乳酸 (Lac) 对肿瘤中的高糖酵解率敏感，因此，我们首先建议开发一种基于 HP 13C MRS 的方法，用于无创评估 ADPKD 中的代谢重编程。具体来说，我们将开发优化的 MR 采集和量化技术，以改进 HP [1-13C] 和 [2-13C]Pyr 及其各自代谢产物的代谢成像同时测量糖酵解和线粒体代谢（目标 1）。其次，我们将在一项纵向研究中评估这些技术检测肾脏代谢的能力 ADPKD 小鼠模型（目标 2）如果成功，HP Pyr 的代谢成像将成为关键。 ADPKD 的临床前和临床研究取得了进展，可以添加到个性化治疗的工具箱中用于病人护理的药物。