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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK069403-08S1
Application #
8838450
Study Section
Special Emphasis Panel (ZRG1-EMNR-R (56))
Program Officer
Hoshizaki, Deborah K
Project Start
2004-12-01
Project End
2016-02-29
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
8
Fiscal Year
2014
Total Cost
$91,100
Indirect Cost
$29,700
Name
University of Pittsburgh
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Sander, Veronika; Davidson, Alan J (2014) Kidney injury and regeneration in zebrafish. Semin Nephrol 34:437-44
Cirio, M Cecilia; de Groh, Eric D; de Caestecker, Mark P et al. (2014) Kidney regeneration: common themes from the embryo to the adult. Pediatr Nephrol 29:553-64
Naylor, Richard W; Davidson, Alan J (2014) Hnf1beta and nephron segmentation. Pediatr Nephrol 29:659-64
Novitskaya, Tatiana; McDermott, Lee; Zhang, Ke Xin et al. (2014) A PTBA small molecule enhances recovery and reduces postinjury fibrosis after aristolochic acid-induced kidney injury. Am J Physiol Renal Physiol 306:F496-504
Sanker, Subramaniam; Cirio, Maria Cecilia; Vollmer, Laura L et al. (2013) Development of high-content assays for kidney progenitor cell expansion in transgenic zebrafish. J Biomol Screen 18:1193-202
Cianciolo Cosentino, Chiara; Skrypnyk, Nataliya I; Brilli, Lauren L et al. (2013) Histone deacetylase inhibitor enhances recovery after AKI. J Am Soc Nephrol 24:943-53
Naylor, Richard W; Przepiorski, Aneta; Ren, Qun et al. (2013) HNF1* is essential for nephron segmentation during nephrogenesis. J Am Soc Nephrol 24:77-87
Swanhart, Lisa M; Cosentino, Chiara Cianciolo; Diep, Cuong Q et al. (2011) Zebrafish kidney development: basic science to translational research. Birth Defects Res C Embryo Today 93:141-56
Hukriede, Neil A; Dawid, Igor B (2011) Making a tubule the noncanonical way. J Am Soc Nephrol 22:1575-7
Cirio, M Cecilia; Hui, Zhao; Haldin, Caroline E et al. (2011) Lhx1 is required for specification of the renal progenitor cell field. PLoS One 6:e18858

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