This Faculty Early Career Development (CAREER) grant will investigate how tissue stiffness regulates the kidney?s ability to filter blood. The kidney continuously purifies the blood to remove toxins and waste while keeping cells and large proteins in circulation. How the kidney performs this essential function is not fully understood. The blood and urine are separated by a thin basement membrane lined with cells. This membrane provides a barrier to the movement of large molecules into the urine. Leakage of proteins across the kidney filter is a primary indicator of kidney damage. It is known that the structural and mechanical properties of the basement membrane are altered in diseases such as Alport syndrome, diabetes, and chronic kidney disease. This research project will increase understanding of how changes in basement membrane stiffness affect protein transport across the kidney filter. This will be accomplished using an integrated experimental approach. The work will combine combines chemical, enzymatic, and genetic methods to modify basement membrane stiffness and bioengineered models of the kidney filter. This award will also promote science and engineering concepts to high school and undergraduate students through implementation of a near-peer mentoring program and development of a cell-basement membrane themed curriculum. There will be an emphasis on engaging socioeconomically disadvantaged and underrepresented minority students.
The overall research goal of this project is to understand how basement membrane mechanics regulates the molecular selectivity of the glomerular filtration barrier. This project will investigate the hypothesis that the mechanical properties of the glomerular basement membrane play a critical role in regulating permeability through two distinct mechanisms: (1) by altering compression-dependent transport across basement membranes and (2) through mechanically mediated effects on glomerular epithelial and endothelial cell function. The first objective is to determine how alterations in stiffness regulate the molecular permeability of biologically derived basement membranes. The second objective will evaluate the effects of basement membrane stiffness on podocyte and glomerular endothelial cell permeability. The third objective is to develop a multilayer bioreactor model of the glomerular filter to evaluate the coordinated role of the basement membrane, podocytes, and endothelial cells in regulating pressure-dependent molecular permeability. These studies aim to provide new fundamental understanding of the basic mechanisms of kidney function and determine how disease-mediated changes in basement membrane stiffness contribute to development of proteinuria.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
