This competitive renewal application continues to address the molecular genetic basis of kidney development and renal epithelial cell regeneration. During previous funding periods, we have made significant breakthroughs in defining the mechanisms of Pax2 protein function in development and disease. The current application will extend and expand our studies in several new directions. First, we will identify and characterize Pax2 target genes in vivo using novel EGFP alleles for identifying mutant cell types. Second, we will determine whether targets activated by Pax2 are direct and require the PTIP/Mll histone methyltransferase complex. The expression of developmental targets will be assessed in animal models of renal disease and in regenerating kidneys. In the second aim, we will screen for inhibitors and activators of Pax2 activity using cell based assays and chemical libraries. We have developed assays for high throughput screening that can detect both activators and inhibitors of Pax2 function. Given all that we know about DNA binding and protein- protein interactions, we will be able to test the mechanisms of inhibition or activation directly. Such small molecules may be very useful for attenuating renal polycystic disease or renal cell cancers, in which Pax2 over expression is a determining factor. The genetic and cell biological mechanisms of renal epithelial cell regeneration are poorly characterized. Our work will define the transcriptional paths required for kidney development and regeneration and can provide new avenues for therapeutic intervention in renal disease.
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 regeneration and cancer. 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 targeted anticancer drugs. This renewal continues to focus on the Pax2 and the genetic network controlling renal epithelial specification. New Pax2 target genes and new models for Pax2 function are being studied in development, in regenerating kidneys, and in kidney disease. How renal epithelial cells are specified and proliferate is essential for understanding abnormal proliferation in a variety of disease states. Furthermore, recruiting the intrinsic developmental program to aid enhance the regeneration of injured kidneys can dramatically alter the way acute and chronic renal disease is currently being treated.
|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|
|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|
|Dressler, Gregory R; Patel, Sanjeevkumar R (2015) Epigenetics in kidney development and renal disease. Transl Res 165:166-76|
|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|
|Soofi, Abdul; Zhang, Peng; Dressler, Gregory R (2013) Kielin/chordin-like protein attenuates both acute and chronic renal injury. J Am Soc Nephrol 24:897-905|
|Xiao, Hong; Yu, Zhigang; Wu, Yipin et al. (2012) A polyglutamine expansion disease protein sequesters PTIP to attenuate DNA repair and increase genomic instability. Hum Mol Genet 21:4225-36|
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