Podocytes are a crucial cell type in the filtering apparatus (glomerulus) of the kidney. The long-term goal of my laboratory's research is to develop new treatments that improve the regenerative capability of podocytes, and thus prevent end-stage renal disease (ERSD). At present, chronic renal disease in children and adults leads to irreversible kidney damage and lifelong dialysis or kidney transplantation. This represents a significant burden for patients and their families, and costs the health care system billions of dollars annually. Over the past several years, it has become evident that irreversible damage to podocyte foot processes (long actin-rich cell extensions) leads to massive loss of protein and ultimately to glomerulosclerosis and ESRD. There exist however clinical conditions (e.g. minimal change disease), in which podocytes are able to recover from transient damage, suggesting that they possess intrinsic mechanisms to re-establish foot process architecture. We have developed evidence that podocytes use cytoplasmic ribonucleoprotein particles (RNPs) or RNA granules to store translationally silent mRNAs within their foot processes for local translation, in a similar manner as another polarized cell type, the neuron. This grant will continue our studies on the role of RNA granules as an adaptive mechanism involved in maintaining foot process architecture and thus preventing ESRD. Two major foci will be on the role of the RNA binding protein Staufen 2 in regulating mRNA localization in podocytes and the role of Staufen 2 and Staufen 2-associated miRNAs in the cytoskeletal assembly of podocyte foot processes both under physiological conditions and in response to injury. A greater understanding of this physiologic pathway may eventually result in the design of new therapeutic agents that will prevent irreversible damage to podocyte foot processes and ESRD.
This grant explores the concept that podocytes transport and store translationally silent mRNAs in their foot processes. This mechanism may enable podocytes to respond to physiologic stimuli through the local translation of proteins that are important in maintaining intact foot process architecture, thus preventing glomerular disease. A greater molecular understanding of this process may eventually lead to novel therapeutic approaches to improve the regenerative capability of podocytes, and thus prevent or treat glomerular disease.