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.

Although autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease in humans and is estimated to affect 1/1000 individuals worldwide there is currently no cure and the so far only approved drug only slows down the progression of the disease. Therefore, new tools are necessary to study the pathophysiology of the disease and identify new targets for therapy. The proposed research will address this current need by developing a noninvasive imaging method to investigate metabolic alterations in ADPKD that could be essential in closing knowledge gaps and, ultimately, improving outcomes for patients with ADPKD.