ABSTRACT: Protein kinases control most cellular processes through signal transduction linked phosphorylation networks. Importantly, dysregulated protein kinase signaling is both the cause and consequence of numerous human diseases. Due to the crucial role of kinases in disease pathogenesis, as well as suitable pharmacological properties and clinical safety profile of kinase inhibitors, protein kinases have emerged as attractive therapeutic targets, especially for anti-cancer therapy. However, the underlying biology of the majority of protein kinases, a key gene family within the druggable genome, remains unclear. In addition, the role of protein kinases in the pathogenesis of non-oncological diseases, especially acute kidney injury (AKI), remains underexplored. AKI is a common disorder associated with toxic, inflammatory, and hypoxic insults to tubular epithelial cells. Using a kinome-wide RNAi screen, we recently identified Cdkl5 kinase as a critical regulator of epithelial cell death associated with acute kidney injury (AKI). While Cdkl5 kinase has been previously studied for its role in brain development, very little is known about the other four members of the cyclin-dependent kinase-like (Cdkl) family. Our preliminary results show that Cdkl1 kinase is activated under stress conditions associated with AKI and RNAi mediated Cdkl1 knockdown protects epithelial cells from nephrotoxic injury. Through chemical genetics approach, we have also identified Sox11 as a novel Cdkl1 substrate. We hypothesize that Cdkl1 is a stress- responsive kinase that phosphorylates Sox11 resulting in suppression of a protective transcriptional regulator, contributing to epithelial dysfunction and cell death. In the current proposal, we aim to test our hypothesis by examining the consequences of Cdkl1 gene ablation on the severity of AKI (Aim 1) and utilize biochemical and cell biological approaches to probe the functional consequences of Cdkl1 mediated Sox11 phosphorylation on stress-induced renal epithelial cell death (Aim 2). These studies will lead to the development of critical experimental tools that are expected to accelerate future studies into the biological functions of Cdkl1 kinase. Finally, these studies are expected to reveal the role of Cdkl1 kinase in kidney injury and illuminate the physiological role of an important member of the enigmatic Cdkl family of kinases.