Metabolic imaging of hyperpolarized 13C pyruvate in polycystic kidney disease

回应NIDDK NOT-DK-20-034《进展中的多囊肾病(PKD)研究》 通过催化工具和技术开发“，这项建议的总体目标是开发新的 代谢成像工具用于研究PKD的代谢改变。常染色体显性遗传性PKD 是最常见的遗传性肾脏疾病，估计全世界有1/2500至1/1000人受到影响。 然而，目前还没有治愈方法和额外的治疗方法可以完全延缓或预防肾囊肿。 编队仍然是一个未得到满足的临床需求。最近，人们对改变的方面越来越感兴趣 囊性细胞中的代谢，有多条证据表明代谢重新编程是一种 这种疾病的内在成分。更好地理解代谢紊乱与疾病的关系 膀胱发生可以帮助确定新的治疗靶点。一个重要的发现是， ADPKD基因PKD1的缺失以类似于Warburg效应的方式上调糖酵解的速度 在肿瘤细胞中。然而，目前研究ADPKD代谢过程的方法的局限性是 他们不像依赖体外测试那样测量正常微环境中的细胞新陈代谢。这个 超极化(HP)~(13)C磁共振波谱(MRS)的最新发展首次使实时 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[1-13C]丙酮酸(PYR)，临床前和临床研究都表明其 转化为乳酸(Lac)对肿瘤中的高糖酵解率很敏感。因此，我们建议首先 开发一种基于HP 13C MRS的方法，用于无创评估ADPKD的代谢重编程。 具体地说，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改变的能力 ADPKD小鼠模型(目标2)。如果成功，HP PYR的代谢成像将代表着一个关键的 ADPKD的临床前和临床研究进展，可增加个性化工具箱 治疗病人的药物。

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.