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 clathrin mediated endocytosis orchestrating podocyte function. Using genetic mouse models, we have discovered proteins involved in mediating clathrin mediated endocytosis such as synaptojanin 1, dynamin, and endophilin, are indispensible for maintaining a normally functioning filtration barrier. We have further extended our findings that GAK, a protein important for uncoating clathrin, is equally important. To probe the mechanism, a microarray analysis on enriched glomeruli was performed revealing a plethora of actin-regulated genes containing a serum response element regulated by the serum response factor. We have also taken advantage of human kidney biopsies from patients with focal segmental glomerulosclerosis (FSGS), which also demonstrated reduced GAK expression and increased serum response factor expression. Therefore In Aim 1, we will define the fundamental mechanisms on how loss of GAK contributes to podocyte dysfunction through abnormal actin dynamics mediated by serum response factor.
In Aim 2, we will characterize the role of GAK's C-terminus to stabilize podocyte function and further investigate the link between endocytosis and actin in podocytes. Our mouse models of disease with human FSGS biopsy findings provide impetus to further define the role of clathrin- mediated endocytosis in the formation and maintenance an intact glomerular filtration barrier.
Damage to the kidney filtration barrier resulting in urinary protein loss accounts for approximately 80% of end stage kidney disease where nearly 600,000 patients in the United States require dialysis or kidney transplantation. Understanding the fundamental biology is a necessity as currently, there is a lack of therapeutic options. In this grant proposal, we plan to elucidate the underlying components required to maintain a normally functioning filtration barrier, so that novel treatments can be discovered in the near future.
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