Metabolic imaging of hyperpolarized 13C pyruvate in polycystic kidney disease

针对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 研究PKD代谢改变的代谢成像工具。常染色体显性遗传PKD（ADPKD） 是最常见的遗传性肾病，估计影响全世界1/2500至1/1000的个体。 然而，目前还没有治愈和额外的治疗，将完全延迟或预防肾囊肿 但是，临床上的需求仍然没有得到满足。最近，人们对改变的生物学的各个方面越来越感兴趣。 有多条证据表明，代谢重编程是一种新的代谢途径， 疾病的内在组成部分。更好地理解代谢失调与 囊肿形成可以帮助确定新的治疗靶点。一个重要的发现是， ADPKD基因PKD 1的缺失以类似于瓦尔堡效应的方式上调糖酵解速率 在肿瘤细胞中。然而，目前研究ADPKD代谢过程的方法的局限性在于， 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。的 超极化（HP）13 C MR波谱（MRS）的最新发展首次实现了实时 体内关键动态代谢过程的非侵入性测量。到目前为止，使用最广泛的 底物是[1- 13 C]丙酮酸（Pyr），临床前和临床研究均表明， 转化为乳酸（Lac）对肿瘤中的高糖酵解速率敏感。因此，我们建议首先 开发一种基于HP 13 C MRS的方法，用于非侵入性评估ADPKD的代谢重编程。 具体而言，我们将开发优化的MR采集和量化技术，以改善 HP [1- 13 C]和[2- 13 C]Pyr及其各自代谢产物的代谢成像， 糖酵解和线粒体代谢的同时测量（目的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改变的能力， ADPKD的鼠模型（Aim 2）。如果成功，HP Pyr的代谢成像将代表一个关键的 ADPKD的临床前和临床研究都取得了进展，可以添加到个性化的工具箱中。 用于病人护理的药物。

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.