Project Summary Chronic kidney disease (CKD) often leads to irreversible deterioration of kidney function that often progresses to End Stage Kidney Disease (ESKD). CKD has emerged as a serious public health issue and data obtained from the USRDS reveals that the number 20 million patients in the United States suffer from CKD. As glomerular diseases secondary to podocyte dysfunction account for greater than 80% of all CKD, an intensive molecular and genetic approach to identify mechanisms for podocyte development, maintenance and repair may provide new therapeutic targets Recent evidence suggests an important role of glomerular injury exacerbated by calpain activation. Using a unbiased screen, we have identified Pfn1, as potentially a critical gene to maintain the integrity of the glomerular filtration barrier. Loss of PFN1 in human podocytes resulted in multinucleated cells, increased calcium, and calpain 2 activation. Therefore, In Aim 1, we will define the fundamental mechanisms on how loss of Pfn1 contributes to podocyte dysfunction through characterizing the new generated knockout mice. In Aim 2, we will characterize the role of Capn2 to stabilize podocyte function and further investigate the link between Pfn1 and Capn2. Our mouse models of disease provide impetus to further define the role of Pfn1 and Capn2 in the formation and maintenance an intact glomerular filtration barrier.