ORCID
https://orcid.org/0000-0002-8235-3998
Date of Award
12-13-2023
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
The kidney is a critical organ responsible for the maintenance of fluid, electrolyte and metabolites in the body. Recent advancements in kidney research, including the use of single-nuclei RNA Sequencing (snRNA-Seq), have uncovered a complex landscape that encompasses both physiological and pathological conditions. The scope of my thesis covers two important aspects: (1) the exploration of kidney sexual dimorphism, (2) a detailed investigation of polycystic kidney disease (PKD). To obtain a comprehensive understanding of the molecular regulation of kidney sexual dimorphism, we integrated single nucleus RNA and ATAC sequencing (snRNA-Seq and snATAC-Seq) and Visium spatial transcriptomics (ST) data to build a spatially resolved cell-type-specific molecular atlas for the mouse kidney throughout the lifespan of both sexes. We demonstrated that proximal tubules (PT) have the most sex-biased differentially expressed genes (DEGs) and are associated with hormone regulations. Specifically, we found that the female-biased DEG Socs2 is potentially upregulated by estrogen indirectly through prolactin-induced Jak2/Stat5 activation. On the other hand, androgen is directly involved in regulating male-biased DEGs. Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder within the kidney, marked by the growth and expansion of spherical cysts. Traditionally, the characterization of the cystic kidney has largely relied on bulk-based technologies such as microarray. While these approaches have provided valuable insights, they come with limitations, as they masked contributions to the overall dysregulated profile from individual cell types. To address such limitations, we utilized a conditional Pkd1 knockout mouse model and applied snRNA-Seq profiling in order to capture intricate molecular changes occurring at different stages of PKD. Within PT populations, we identified mutant-specific genes that are implicated in different disease stages, such as the axonal guidance pathway as a signature of the early stage, whereas kidney damage as a feature for late disease stage. A thorough analysis of the collecting duct principal cells (CD_PC) revealed profound cellular heterogeneity within the mutant samples, adding a new layer to the disease complexity. Additionally, our cell-cell interaction analysis elucidated dysregulated biological processes linked to fibrosis, an important feature in PKD progression. Overall, my thesis provides novel insights into kidney sexual dimorphism and the complexities of ADPKD. The findings emphasize the importance of equal representation of male and female subjects in animal model experimental design, and lay the foundation for targeted and personalized approaches in kidney disease treatment.
Language
English (en)
Chair and Committee
Li Ding
Recommended Citation
Liu, Ruiyang, "Single-nuclei Resolution Kidney Profiling in Physiological And Disease Settings" (2023). Arts & Sciences Electronic Theses and Dissertations. 3177.
https://openscholarship.wustl.edu/art_sci_etds/3177