The kidney has an inherent ability to regenerate following damage. This repair is concomitant with the expression of transcription factor genes such as Pax2 and Lhx1, which are essential for initiating normal kidney organogenesis, suggesting that regenerating tubular cells arise from cells with a primitive, progenitor-like state Renal progenitors may be formed following the "re-programming" of tubular epithelial cells, such as in mammals, or from cells that permanently reside in the kidney, such as in the adult zebrafish. We hypothesize that any treatment that expands or enhances renal progenitors will accelerate the rate of recovery following acute kidney injury (AKI). To test this we developed larval and adult models of AKI in zebrafish and developed unique tools and methodologies to manipulate renal progenitors. We performed a high-content screen to identify compounds that enhance renal progenitor cell number and identified a novel class of histone deacetylase inhibitors (HDACis), the PTBAs, that accelerates renal recovery in zebrafish and mouse models of AKI when given after the induction of injury. The proposed revision will focus on the mechanism of action for PTBA class compounds and is divided into three sub-aims, which take advantage of the complementary expertise of investigators at two different institutions. Sub-Aim 1: We will test if PTBA treatment drives G2/M escape vs. S phase arrest in AKI models. Sub-Aim 2: We will identify transcriptional targets of PTBA treated PTECs. Sub-Aim 3: We will perform functional analysis of candidates that promote G2/M checkpoint escape.
Acute kidney injury (AKI) is a common and largely reversible disorder that has a high mortality but for which there is no specific treatment in humans. Our studies have identified a new class of histone deacetylase inhibitors, the PTBAs, which accelerate the rate of renal recovery following AKI. The purpose of our proposed revised/supplemental studies is to determine the molecular mechanism by which these agents act to enhance renal regeneration with the ultimate goal of developing new therapies to treat AKI.
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