Universität zu Köln

Padvitski, Tsimafei ORCID: 0000-0001-9528-8657 (2025). Transcriptional Regulation and Single Cell Damage Score in Podocytes. PhD thesis, Universität zu Köln.

PDF PhD_thesis_Padvitski_pub.pdf Download (24MB)

Abstract

It is estimated that around 10% of the global population is affected by chronic kidney disease (CKD), placing a significant burden on healthcare systems worldwide (Francis et al. 2024). Among the causes of CKD, 90% are attributed to glomerular diseases, in which podocytes are damaged and lost (Wiggins 2007). Podocytes are terminally differentiated visceral epithelial cells, which play a crucial role in establishing the selective permeability in the glomerulus. Recent large-scale transcriptomic approaches in mice and humans have demonstrated that alterations in the glomerular transcriptional program are a pivotal feature of numerous diseases affecting podocytes. In this thesis, I investigate the transcriptional regulation of healthy and damaged podocytes through multiple approaches. First, I analyzed novel bulk RNA sequencing data from glomeruli to characterize transcriptional changes resulting from perturbation of the Wt1 transcription factor, a critical regulator of podocyte biology. I then leveraged novel ChIP-seq data to explore how podocyte damage rewires the transcriptional network, focusing on interactions regulated by Wt1 and co-regulated by Tead1. Second, using single-nucleus RNA sequencing (snRNA-seq), I distinguished podocyte-specific transcriptional changes from shifts in cellular composition induced by podocyte injury. Third, I developed a universal metric of podocyte health, termed the podocyte damage score (PDS), using transcriptomic data from published sources. Applying the PDS to single-cell RNA sequencing datasets from various podocyte damage models allowed us to identify both universal and model-specific features of the transcriptional response to injury. Additionally, by integrating these findings with a podocyte transcriptional regulatory network (TRN) constructed from podocyte-specific ATAC-seq data and transcription factor motifs, I characterized the transcriptional regulators involved in podocyte transcriptome rewiring under damage conditions. In conclusion, this research advances our understanding of gene regulation in healthy and damaged podocytes and establishes methodologies for studying cell-specific mechanisms of disease at the single-cell level. It is my hope that these findings will contribute to the development of new therapeutic strategies for CKD.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Padvitski, Tsimafei tsimafeipadvitski@gmail.com orcid.org/0000-0001-9528-8657 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-748735
Date:	2025
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases
Subjects:	Life sciences
Uncontrolled Keywords:	Keywords Language Gene regulation English Kidney English Cell damage English
Date of oral exam:	9 December 2024
Referee:	Name Academic Title Beyer, Andreas Prof.Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/74873