Using spatially resolved functional genomics to dissect mechanisms of chronic kidney disease and identify novel therapeutic targets

• Applicant: Professor Dr. Christoph Kuppe
• Subject Area: Nephrology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 459969915

Chronic kidney disease (CKD) represents a complex syndrome characterized by persistent alterations in kidney structure and function with limited treatment options for the patients. During CKD progression different compartments in the kidney (glomeruli, tubuli) react with stereotypic responses of organ injury (maladaptive) or repair processes (adaptive) (e.g. glomerulosclerosis or tubulointerstitial fibrosis). These responses however happen simultaneously in different renal compartments and spatial locations complicating the identification of unifying therapeutic targets. How these mechanisms are molecularly controlled on a cellular level and how these processes develop in the different compartments of the kidney is currently unknown. A better understanding of adaptive and maladaptive processes within their spatial and cellular context could lead to a better understanding and the identification of novel therapeutic targets for kidney disease. In order to investigate the molecular mechanisms in a compartment-specific way we will use cutting-edge genomic technologies to unravel mechanisms of CKD focusing on spatially resolved cellular crosstalk, that drive kidney functional loss. We will use novel transcriptome and epigenome single-cell technologies that allow us to study kidney cells in a compartment-specific manner by isolating single glomeruli and single tubuli from different mouse models of kidney injury. Next, we will use transgenic reporter mice and isolate cellular complexes using FACS to study cell-cell communication with high resolution. In order to map these cellular complexes back into their spatial tissue context, we will use spatial gene expression data and an integrative data analysis approach that allows us to map the single-cell data back into space. We will use human kidney tissue derived from nephrectomies for the same approach to map cellular-crosstalk with a high-resolution with a spatial context. Next, this data will be mind to identify novel therapeutic targets. Using DNA-barcoded compound screens we will identify small-molecular binders and validate them using different human kidney cell lines, human iPSC-derived organoids, and human kidney cells derived organoids as 3D in-vitro model systems. This cutting edge methodology will guide the development of novel therapeutics for the vast and growing patient population suffering from CKD.

• DFG Programme: Independent Junior Research Groups