Mesenchymal Folliculin Defects as a Novel Pathogenic Mechanism of Polycystic Kidney Lesions
Abstract
This research project will address one of the FY20 PRMRP Topic Areas, “Polycystic Kidney Disease.” Polycystic kidney disease (PKD) is a common genetic disease, affecting both adults and children, which can lead to kidney failure and other severe complications. Classically, PKD is believed to be a disease of the epithelial cells of the kidney. Epithelial cells line the surfaces of the kidney and are responsible for modulating the substances that end up in the urine (for example, determining how much sodium ends up in the urine). This project is focused on the kidney mesenchyme: a completely different cell type that has never before been suspected to contribute to PKD. Kidney mesenchyme cells fill up the spaces between the epithelial cells and include the cells that line blood vessels and lymphatic vessels. Kidney mesenchyme serves many critical roles, including supporting the epithelium when injury occurs. Mesenchymal cells are also critical during the development of many organs of the body, secreting substances that “signal” to other cell types. The preliminary data that form the foundation of this project indicate that abnormalities in kidney mesenchyme can lead to extensive epithelial cysts during the first few weeks of life in mice. This cellular “cross-talk” as a cause of PKD is highly novel. This project will identify the specific type of mesenchymal cell(s) that can lead to epithelial cysts, and identify the specific cellular and molecular mechanisms that cause cyst formation in this novel model of PKD. This model has knockout of a gene called folliculin (Flcn). In humans, mutations in folliculin cause a hereditary disease that is associated with kidney cysts. The cellular pathways that are already known to be regulated by folliculin provide a starting point for identifying these mechanisms. We will also use state-of-the-art single cell RNA sequencing to identify the mesenchymal cells that cause the cysts and the molecular mechanisms. This innovative research project is both high-risk and high-reward. The cellular mechanisms that underlie PKD in this model are completely novel and represent a “high-risk” new direction, away from the conventional model in which PKD is driven by the epithelial cell compartment. The rewards are also high in terms of truly understanding the fundamental cells and pathways that contribute to cyst pathogenesis. We hypothesize that the mesenchymal compartment contributes to cyst pathogenesis in many different contexts, including those diseases that are believed to be primarily driven by the epithelial compartment, such as autosomal dominant PKD (ADPKD). Ultimately, understanding the full picture of cyst pathogenesis could lead to high-impact advances for both children and adults affected by PKD.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110257
Entities
People
- Wei Shi
Organizations
- United States Army