Ischemia and reperfusion is a leading cause of acute kidney failure. Proximal tubular epithelial cells are most sensitive to this stress. The ability of injured tubular epithelial cells to recover and proliferate is crucial for restoration of kidney function. Mechanisms of epithelial tubular cells regeneration are not well understood. Recent discoveries implicate a regulatory role for chromatin and histone H4 acetylation in the cell cycle progression. The broad long-term goal of this project is to determine the role of the JADE1-HBO1 Histone Acetyl Transferase (HAT) complex in regulation of DNA replication and cell growth in normal and injured kidney epithelial cells. The HAT activity of HBO1 has been implicated in promotion of DNA replication and cell cycle progression. However, little is known regarding the mechanisms that regulate HBO1-dependent DNA replication and integrate epigenetic control of DNA replication with other cell cycle events. We have identified JADE1 as a novel regulatory binding partner of HBO1 that is necessary for HAT activity of the HBO1 complex. The central hypothesis to be tested is that JADE1 regulates DNA replication and cell cycle progression in an HBO1-dependent manner. We further hypothesize that JADE1-HBO1 interactions and activity is most likely important for kidney epithelial cells regeneration after hypoxia and reperfusion injury. SA1 will test the hypothesis that JADE1 promotes HBO1-dependent DNA replication and cells proliferation. These experiments will determine the consequences of JADE1 status on the ordered control of DNA replication and cell cycle control. SA2 will test the hypothesis that replication and cell cycle progression are regulated in part via CDK- mediated JADE1 phosphorylation. Experiments therein will determine the significance of novel CDK-dependent JADE1 phosphorylation events that we have identified. SA3 will test the hypothesis that JADE1-HBO1 is required for the regeneration of tubular epithelial cells after hypoxia and reperfusion stress. Experiments in this SA will determine mechanism by which JADE1-HBO1 regulate cell cycle during hypoxia and reperfusion stress. In addition, these experiments will determine effects of HBO1-JADE1 status on the recovery of tubular epithelial cells after the stress. The results of this study might define a novel mechanism of HBO1-mediated DNA replication and tubular epithelial cells regeneration. In addition, the results of these studies might link JADE1 and HBO1 with diseases associated with impaired cell cycle, including cancer, degenerative diseases and stress-induced cellular injury. The result of this work may identify JADE1 and HBO1 as novel drug targets that will promote epithelial tubular cells recovery after the injury.
Mechanisms and consequences of acute toxic injury to the kidney tubular epithelial cells are being elucidated. Novel chromatin-mediated mechanism of kidney tubular cells injury and recovery caused by ischemia and reperfusion is being developed. The proposed studies might uncover novel marker of acute renal failure and potential target for drug development.
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