Targeting Parietal Epithelial Cells in FSGS
Abstract
Although chronic kidney disease is increasing annually in the US, now impacting at least 1 in 10 people, it has increased disproportionately in US Veterans. Approximately 80% of patients with kidney disease die from cardiovascular complications before they reach dialysis. The leading cause of kidney disease in Veterans who have protein in their urine is a condition called focal segmental glomerulosclerosis (abbreviated as FSGS), which is one of the Fiscal Year 2018 Peer Reviewed Medical Research Program Topic Areas. FSGS is synonymous with progressive scarring of the kidney’s filtering units called glomeruli. Scarring compresses these highly functioning filtering glomeruli and over time reduces their ability to filter out the body’s toxins, which we then call chronic kidney disease. The challenge for clinicians is to stop and even reverse scarring, as no known therapies exist today. In this grant application, we will test the hypothesis that we can influence the cellular behavior in the glomeruli of FSGS patients by promoting their repair and inhibiting scaring in the filtering units that are injured. In the first specific aim of the grant, we will study one particular cell type in the filtering units called the podocyte. It is the main cell type injured in FSGS and it normally dies upon injury, leading to a decrease in podocyte numbers. Unfortunately, these highly specialized cells cannot replace themselves because they cannot divide. Thus, their replacement is totally dependent on neighboring stem cells called parietal epithelial cells (PECs), which to a limited extent can become like podocytes. Our goal in this aim is to ramp up the ability of these PECs to become podocytes and replace the diseased ones by a combination of exogenously added small molecules. In the second aim of this grant, we will investigate a second property of PECs also affected in FSGS, which is that they become activated and in doing so contribute to the scarring process, which will decrease kidney function over time. We will test the hypothesis that we can interfere with this activation processes of PECs again using a combination of exogenously added small molecules, and in doing so, decrease scar tissue formation. To test both hypotheses, we will use a unique approach that combines the study of human podocytes and PECs in sophisticated bio-engineered cell culture devices and use state-of-the-art technologies to analyze their gene profiles before and after exposure to exogenously added small molecules. In addition, we will use a unique mouse, which we have developed to specifically and permanently label podocytes and PECs with a green and red color, respectively. This allows us the directly follow the impact of FSGS and the therapeutic benefit of our combinations of exogenously added small molecules on replenishing podocytes or deactivating PECs to reduce scarring. Our overall goal is to use these preclinical studies to discover new therapies for patients with FSGS so that clinical studies can then be conducted to improve their quality and quantity of life.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910024
Entities
People
- Stuart Shankland
Organizations
- United States Army
- University of Washington