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 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 Previous evidence has suggested the importance of endocytic trafficking in podocytes, Using a unbiased screen, we have unearthed Lrp1 within clathrin coated vesicles, and as a potentially important gene to maintain the integrity of the glomerular filtration barrier. Loss of Lrp1 specifically in mice podocytes resulted in proteinuria and progression of CKD. Therefore, In Aim 1, we will define the fundamental mechanisms on how loss of Lrp1 contributes to podocyte dysfunction through characterizing the newly generated knockout mice. In Aim 2, we will determine how Lrp1 signaling plays a potential role in dsDNA repair by examining genes critical for nonhomologous end joining Setd1a and Lig4, and test SP16, a FDA approved Lrp1 agonist in the treatment of mouse models of glomerular injury.