Spatial Multi-Omics to Profile Metabolic Pathways for Kidney Disease - Project Summary/Abstract The Kidney Precision Medicine Project (KPMP) is an NIDDK funded program that, in part, aims to generate a human Kidney Tissue Atlas. In the initial UG3/UH3 KPMP program, our Tissue Integration Site (TIS) implemented and streamlined spatial metabolomics and lipidomics technologies based on matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) and set up a quality-controlled pipeline for high throughput analysis of human kidney biopsies. We also developed new bioinformatic methods for confident molecular annotations of our MALDI-MSI data, as well as new visualization tools that permitted molecular image overlay on optical images (e.g., histopathological images) using METASPACE– a cloud software for molecular annotation, visualization, and data sharing. As such, these three technologies were sufficiently validated for KPMP data collection on kidney biopsy tissue and approved by the Tissue Interrogation Site Approval Committee (TISAC). We also developed a new platform for spatial profiling the kidney glycome that is currently under review for TISAC approval. In close collaboration with other TISs and the Data Visualization Center, our TIS has been able to demonstrate the unique value of connecting hundreds of bioactive molecules to genes and proteins and to infer functional relationships at the renal compartment and cellular level, capacities critically needed for the human Kidney Tissue Atlas. Our team combines the expertise of the University of Texas Health San Antonio and Pacific Northwest National Laboratory in nephrology and spatial omics, the European Molecular Biology Laboratory in molecular data annotation, management, and visualization, and the Icahn School of Medicine at Mount Sinai in integrating multi-omics data. We are uniquely positioned to generate spatial multi-omics interpretation describing kidney metabolism and to contribute to the Kidney Tissue Atlas. The overarching goals of the project are to generate spatial multi-omics data from KPMP kidney biopsies to elucidate pathways related to acute kidney injury (AKI), hypertensive chronic kidney disease (H-CKD), and diabetic kidney disease (DKD), to define disease subgroups on the spatial and single-cell level, and to interrogate drug metabolism. We will achieve this through two main project aims: (1) scaling up, improving, and validating spatial omics technologies, and (2) developing and validating bioinformatics for pathways analysis and multi-level data integration. For each of the spatial omics platforms, we expect to reach throughput to analyze up to two kidney biopsies per week with a spatial resolution of ≤10 µm. We will focus on developing the necessary bioinformatics and data management methods and workflows to extract the molecular knowledge for integration into the Kidney Tissue Atlas in collaboration with the Kidney Tissue Atlas Coordinating Center, and we will develop integrative bioinformatics for pathway analysis and drug metabolism. Our proposed program within the next phase of KPMP will provide an essential contribution to the Kidney Tissue Atlas, will deliver clinically relevant molecular data and methods, and provide a FAIR data resource paving the way towards novel precision therapies against AKI/H-CKD/DKD.
