Project Details
Projekt
Integrative high-resolution multi-omics and targeted approaches in patients with IgAN
Subject Area
Nephrology
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 445703531
Immunoglobulin A nephropathy (IgAN) is the most common glomerular disease worldwide. The concept of IgAN pathophysiology focuses on a “four-hit model" with production of galactose deficient IgA1 (Gd-IgA) as the first precipitating event. However, many questions remain unanswered, including the causes for the development of Gd-IgA, the role of the intestinal immune system, or the pathophysiological consequences of Gd-IgA deposition in the kidney. This results in an incomplete understanding of CKD progression in IgAN and a lack of biomarkers to early identify patients at risk and guide therapy.We contributed to clinical studies suggesting a gut-kidney axis in IgAN and defined pathways of intestinal IgA responses. Characterizing peripheral blood mononuclear cells of IgAN patients by single cell sequencing, we observed profound gene dysregulation in plasma cells, further highlighting the key role of plasma cell responses in IgAN pathogenesis. We also developed bioinformatic tools to study intercellular crosstalk and integrate multimodal data in kidney tissue. We hypothesize that the transition of IgAN to a progressive course is reflected by alterations in mucosal immunity and plasma cell functions.We will combine our expertise in clinical nephrology and IgAN research (Seikrit), bioinformatics (Hayat), mucosal immunology and IgA biology (Pabst) with the broad methodological armamentarium of our consortium. In WP1, we will collect biomaterial and patient data, including patients treated with the newly approved drugs targeted release (Trf-) budesonide and sparsentan. Collaboration within the consortium will provide high resolution spatial information of kidney microvasculature (with P7), and glomerular filtration capacities. WP2 will investigate molecular changes and intercellular crosstalk in IgAN by single-cell and high-resolution transcriptomics and pathomics techniques (with P2 and P4). In WP3, we will define the functional characteristics of IgA-secreting intestinal plasma cells, focusing on the quality and quantity of IgA production, specificity for gut microbiota, and control of IgA secretion. In WP4, we will use and further develop computational frameworks to integrate multi-omics data, including single-cell and spatial transcriptomics (with P2), proteomics (with P3), pathomics and imaging (with P4 and P7), and clinical data to better understand the potential link between plasma cell changes and IgAN, to identify molecular signatures of CKD progression in IgAN and potentially identify biomarkers for patient stratification. In conclusion, P8 will contribute to new insights into the pathophysiology of the gut-kidney axis, the plasma cells and, ultimately, the CKD transition in IgAN.
DFG Programme
Clinical Research Units
