A limited understanding of clinically relevant signaling pathways has limited the development of therapeutic agents for human glomerular disease. Our long-term goal is to enhance the pipeline of putative therapeutic targets available to tackle human glomerular disease by elucidating the details and functional significance of key signaling pathways that regulate podocyte injury and survival. Our preliminary data have identified YAP, the key effector of the Hippo signaling pathway, as an important regulator of podocyte survival. YAP inactivation in podocytes causes FSGS in mice and decreased YAP expression is associated with the development and progression of human glomerular disease. We have detected increased intracellular calcium uptake and marked upregulation of calcium-gated potassium channel expression in YAP silenced podocytes. The overall objective of this application is to define the mechanism by which YAP regulates podocyte survival and test its role as a potential therapeutic target. Our central hypothesis is that YAP is inactivated in podocytes by canonical phosphorylation and cytoplasmic sequestration under the influence of the Hippo kinase LATS. YAP expression and function can also be regulated at the genetic and transcriptional level. Decreased YAP signaling enhances purinergic receptor-mediated calcium uptake in podocytes and calcium-gated potassium channel activation contributing to disruption of the actin cytoskeleton. The rationale for the proposed research is that defining the underlying mechanisms that regulate YAP function will advance understanding of glomerular disease progression as well as the quest for novel therapeutic targets available for clinical use. Our hypothesis will be tested by pursuing two specific aims:
Aim 1 will explore the functional significance of YAP phosphorylation and nuclear-cytoplasmic shuttling in podocyte survival. We will determine whether cytoplasmic YAP expression in podocytes enhances injury susceptibility and enhancing nuclear YAP signaling is protective in proteinuric kidney disease. We will also develop a novel YAP agonist and test its role in protecting podocytes from injury.
In Aim 2 we will determine the key signaling pathways and cellular structural changes induced by YAP inactivation. Our innovative approach utilizes state of the art microfabricated 3-D chips, electrophysiology and atomic force microscopy to quantify the biophysical properties of podocytes during YAP inhibition and activation under normal and disease conditions. By homology modeling, we will generate novel small molecule YAP agonists that could be protective in proteinuric kidney disease. These contributions are significant because they have the potential to not only advance understanding of the pathogenesis of glomerular disease but could help identify novel therapeutic targets.

Public Health Relevance

Our preliminary data identified the Hippo signaling pathway and its key effector Yes-associated protein (YAP) as a key regulator of podocyte survival and a potential therapeutic target in progressive glomerular disease. The proposed research will advance the currently available knowledge of glomerular disease pathogenesis and serve as a platform for the development of novel therapeutic agents.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Sadusky, Anna Burkart
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Icahn School of Medicine at Mount Sinai
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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