Research & Publications
The primary research focus is to identify the effector molecules, transcription factors, and growth factors that are responsible for the development and progression of renal cysts in autosomal dominant polycystic kidney disease (ADPKD). The research is focused on the identification of specific events that underlie physical remodeling of the normal renal tubular architecture, and the events that are critical for the pathogenic tubular remodeling in ADPKD.
In addition, research is also focused on the application of Imaging mass cytometry to standardize a defined workflow for 2D quantitative assessment of cell location, cell-cell interactions, and cellular responses in relation to the spatial context in human kidney diseases.
Extensive Research Description
The research goal is to understand the pathogenesis of polycystic kidney disease (PKD), a genetic disorder caused by mutations in either Pkd1 or Pkd2 genes, which encode polycystin 1 (PC1) and polycystin 2 (PC2) respectively, affecting the normal architecture of renal tubule, giving rise to ADPKD. Studies have uncovered the critical roles of polycystins and cilia in maintaining the three-dimensional structure of renal tubules. Understanding the mechanism and discovery of molecular determinants of cyst development and disease progression will advance the mechanism-based therapeutic target for the treatment of ADPKD. We have focused these efforts on delineating the role of Mcp1 in promoting macrophage-dependent cyst expansion in PKD and found that proinflammatory macrophages accumulate around the cyst and promote tubular epithelial cell injury. Subsequent switch to an alternative activation of macrophages promotes accelerated cyst growth due to an increase in tubular proliferative rates. High-resolution multiphoton imaging at the earliest phases of cyst formation following knock-out of Pkd1 showed that tubule dilation and epithelial proliferation occur simultaneously, and that dilation was more evident in tubules in which epithelial area had not increased implying proliferation is not a solitary force for tubule expansion. We are investigating the mechanism and the critical events that maintain the normal architecture of renal tubules and identify the critical components that are dysregulated in the absence of polycystins.
Imaging mass cytometry (IMC) is a technique that uses a high-resolution laser combined with a mass cytometer to detect the presence, location, and amount of up to 42 different heavy metal conjugated antibodies hybridized onto a tissue section. Our group has successfully developed IMC and a machine learning algorithm to identify resident kidney cell populations, infiltrating cell populations, and cell activation and injury states in human kidney tissue. Research is focused on the application of IMC and the analysis pipeline for 2D quantitative assessment of cell location, cell-cell interactions, and cellular responses in human kidney diseases.
Epithelial Cells; Kidney; Kidney Tubules; Macrophages; Nephrology; Polycystic Kidney, Autosomal Dominant; Spatial Analysis