A major interest of my laboratory is the role of basement membrane components in kidney function and disease, with particular emphasis on the glomerular basement membrane (GBM) as a component of the glomerular filtration barrier to albumin. Several genetic and acquired diseases of the kidney affect the GBM, causing thinning or thickening. We are focusing on the laminin and type IV collagen components of the GBM that are mutated in Pierson syndrome (a congenital nephrotic syndrome) and Alport syndrome (hereditary glomerulonephritis), respectively. We have produced knockout mice lacking relevant laminin or collagen IV chains to determine their functions in the kidney and elsewhere. We have also generated transgenic mice expressing mutant versions of laminin beta2 to understand why the mutations cause human kidney disease, using both standard transgenesis and CRISPR/Cas9-mediated appraoches. We have performed proof-of-principle studies to show that the abnormal GBM that is present in Alport syndrome can be normalized by restoring expression of the missing collagen IV network.
Another aspect of my research concerns the role of cell-cell junction/polarity proteins in urogenital development. We have generated mice lacking proteins associated with the Scribble complex (including Scribble, discs large 1, and CASK) and find interesting developmental anomalies, including renal hypoplasia or agenesis; defects in maturation of the distal ureter and its connection to the bladder; and glomerular cyst formation. These defects are observed in human congenital anomalies of the kidney and urinary tract (CAKUT) and in cystic diseases. We are using state of the art methods to investigate the mechanisms for these defects and to determine whether mutations in these genes are involved in human CAKUT.prematurity syndrome, so our studies of the Fatp4 mutant mice have implications for this human disease.
