SPATIAL METABOLOMICS FOR HUMAN KIDNEYS

Acute kidney injury (AKI) and chronic kidney disease (CKD) are major contributors to overall morbidity andmortality in patients in the US. The overall objective of the proposed study is to establish untargeted andtargeted spatial metabolomics analysis of tissues from normal and diseased kidneys to assess cellularmetabolic states associated with healthy function, acute injury, chronic condition, and recovery. We will employultra-high resolving power imaging mass spectrometry (e.g., MALDI-FTICR-IMS) complemented with novelbioinformatics (e.g., METASPACE) for metabolite annotation and big data interrogation strategies to identifyalterations of metabolism in diseased kidneys compared with normal ones. Our Tissue Interrogation Site will bea multi-disciplinary coordinated program composed of leadership in translational nephrology and imaging massspectrometry at UCSD, outstanding facilities for multi-omics analysis at Pacific Northwest NationalLaboratories (PNNL), and bioinformatics for mass spectrometry imaging and 3-D reconstruction housed atEuropean Molecular Biology Laboratories (EMBL). Three specific aims in each phase (i.e., UG3 and UH3) areproposed. In particular, we will establish an untargeted and targeted spatial metabolomics platforms for humankidney interrogation and develop an open bioinformatics platform for data interrogation, 3-D reconstruction,molecular interpretation and public sharing. In the UH3 phase, the untargeted and targeted platforms will bescaled up to improve metabolite coverage and develop key metabolic pathways for specific renalcompartments in kidneys from individuals with AKI, CKD, and disease subgroups. Moreover, the bioinformaticsplatform will also be scaled up to establish 3D (a next-generation technology) metabolite-based maps of kidneystructure in normal and diseased kidneys. A web-service SM-Kidney will be implemented as the online platformto have all the datasets and the results publicly sharable. We will contribute and collaborate with the CentralHub (CH) to integrate our service for the formation of a molecular kidney atlas. With strong collaborationsamong the key personnel from UCSD, PNNL, EMBL, and other universities, institutes, and industry partners,our multidisciplinary team will reach key milestones during both the UG3 and UH3 phases. Milestones include1) the development of a comprehensive untargeted database of metabolite annotations in the normal humanrenal compartments, 2) targeted spatial metabolomics analysis for selected classes of metabolites andpathways, 3) methods and SOPs that meet rigorous QC standards for tissue procurement, initial processingand IMS with optical imaging and 4) providing the online service SM-Kidney with a graphical user interface toevalaute spatial metabolic profiles associated with kidney disease and pathogenesis. All protocols, samples,data, and metabolite atlas of normal, AKI, and CKD samples will be shared across the KPMP.