This competitive renewal application leverages our knowledge of kidney development to develop new strategies for addressing unmet needs in clinical nephrology. The lab has discovered critical genes and pathways that determine renal epithelial cell differentiation, growth, and survival. Many of these same pathways are important for renal cell regeneration and are deregulated in renal disease. During previous funding periods, we have made significant breakthroughs in defining the mechanisms of Pax2 protein function in development and disease. Pax2 is essential for specifying renal epithelial cells in development, is repressed in adult nephrons, but is reactivated in regenerating proximal tubules after injury.
Our first aim will identify key targets of Pax2 regulation in development and in regenerating kidneys. We will test the interactions of Pax2 with epigenetic complexes and determine the function of Pax2 in regenerating tubules.
The second aim capitalizes on our knowledge of Pax2 mediated gene regulation to identify small molecules that can attenuate Pax2 dependent gene expression. We have developed assays that can identify both enhancers and inhibitors of Pax2 function. Unbiased high throughput screens will be carried out to identify hits that modify Pax2 activity. Such hits can be fully characterized at the biochemical level, usin our established models of Pax2 function. Furthermore, computational methods based on homology modeling will be used to identify small molecule inhibitors for Pax2. Such inhibitors could be the basis for novel therapies against polycystic kidney disease or renal cell cancers in which high levels of Pax2 expression persist.

Public Health Relevance

The development of the mammalian urogenital system requires precise genetic networks to activate or repress specific genes, both spatially and temporally, so that growth, differentiation, and patterning are achieved in highly reproducible manner. Any perturbations of such networks can result in congenital defects, such as hypoplastic and cystic kidneys, hydronephrosis, ureteral obstructions, embryonal carcinomas, and lower urinary tract malformations. Furthermore, the genetic networks that control development are also important in adult tissue regeneration and renal cancers. Thus, understanding the genetic and biochemical mechanisms that underlie urogenital development is essential not only for a basic science perspective but also for framing the context of regenerative medicine, for developing novel biological therapies, and for designing tissue- specific anticancer drugs. This renewal extends our knowledge of Pax2 and the genetic network controlling renal epithelial specification in development and regeneration. Using novel genetic mutations and biochemical methods, we will define the functions of Pax2 in embryonic progenitor cells and in regenerating kidney epithelial cells. We will define the genetic and biochemical interactions of Pax2 with epigenetic modifying complexes in kidney epithelial cells and leverage that knowledge to identify and design novel Pax2 modifying compounds. Assays developed in the lab can be used for high throughput screening and for rational drug design such that both enhancers and inhibitors of Pax2 can be developed. Enhancers may be able to recruit the intrinsic developmental program to stimulate regeneration of kidney epithelial cells after injury, whereas inhibitors can be used to suppress abnormal growth in polycystic kidney diseases or renal cancers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054740-18
Application #
9440412
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Hoshizaki, Deborah K
Project Start
1999-01-15
Project End
2020-02-29
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
18
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Grimley, Edward; Liao, Chenzhong; Ranghini, Egon J et al. (2017) Inhibition of Pax2 Transcription Activation with a Small Molecule that Targets the DNA Binding Domain. ACS Chem Biol 12:724-734
Soofi, Abdul; Wolf, Katherine I; Emont, Margo P et al. (2017) The kielin/chordin-like protein (KCP) attenuates high-fat diet-induced obesity and metabolic syndrome in mice. J Biol Chem 292:9051-9062
Soofi, Abdul; Wolf, Katherine I; Ranghini, Egon J et al. (2016) The kielin/chordin-like protein KCP attenuates nonalcoholic fatty liver disease in mice. Am J Physiol Gastrointest Liver Physiol 311:G587-G598
Dressler, Gregory R; Patel, Sanjeevkumar R (2015) Epigenetics in kidney development and renal disease. Transl Res 165:166-76
Abraham, Saji; Paknikar, Raghavendra; Bhumbra, Samina et al. (2015) The Groucho-associated phosphatase PPM1B displaces Pax transactivation domain interacting protein (PTIP) to switch the transcription factor Pax2 from a transcriptional activator to a repressor. J Biol Chem 290:7185-94
Ranghini, Egon J; Dressler, Gregory R (2015) Evidence for intermediate mesoderm and kidney progenitor cell specification by Pax2 and PTIP dependent mechanisms. Dev Biol 399:296-305
Patel, Sanjeevkumar R; Ranghini, Egon; Dressler, Gregory R (2014) Mechanisms of gene activation and repression by Pax proteins in the developing kidney. Pediatr Nephrol 29:589-95
Schwab, Kristopher R; Smith, Gary D; Dressler, Gregory R (2013) Arrested spermatogenesis and evidence for DNA damage in PTIP mutant testes. Dev Biol 373:64-71
Zhang, Peng; Dressler, Gregory R (2013) The Groucho protein Grg4 suppresses Smad7 to activate BMP signaling. Biochem Biophys Res Commun 440:454-9
Patel, Sanjeevkumar R; Dressler, Gregory R (2013) The genetics and epigenetics of kidney development. Semin Nephrol 33:314-26

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