application) The overall goal of our research is to identify novel zinc-finger genes within the kidney to establish their role during nephrogenesis and to identify their target genes that may be up- or down-regulated by these zinc-finger proteins.
The specific aim of this research is to identify the role of Bean2 and Bean3 (two novel Kruppel zinc-finger genes) during nephrogenesis and to identify the target genes they may regulate. To characterize these two novel genes our specific aims are: 1) To identify the genes that are up- or down-trans-regulated by the interaction of zinc-finger proteins and DNA-binding domains of Bean2 and Bean3. The identification of specific DNA-binding sites recognized by the Bean2 or Bean3 zinc-fingers will be our initial step in the identification of known and potentially new genes that are transcriptionally regulated by Bean2 or Bean3 proteins during kidney development. 2) To define the transcription regulation functions of the homeo domains (POZ or KRAB) in the amino termini of Kruppel zinc-finger proteins. Characterizing the role of these two domains will provide information on their regulatory activity, either by identifying those molecules interacting with the KRAB domain of Bean2, or by identifying the capability of the POZ domain of Bean3 forming homo or hetero, protein-protein complexes. These results will indicate at what level of the transcription regulation these domains from the Bean2 and Bean3 novel genes are working during kidney development. 3) To identify the spatial and temporal expression of Bean2 and Bean3 during embryonic development. The results of these studies should complement our efforts to identify the Bean2 and Bean3 target genes by providing information on the location of their expression. We expect that the characterization of these two new zinc-finger genes and identification of their target genes will provide important foundational information necessary to understand transcriptional regulation by zinc-fingers during kidney development. The genes responsible for cell differentiation during development may well be the same genes that regulate the mechanisms that repair the kidney after injury. It is evident that transcription factors are important regulatory switches in the processes of development. In addition, it has recently been found that injured kidneys regress to early developmental stages. Therefore, the elucidation of the function of the transcription factors Bean2 and Bean3 will bring to light a better understanding of nephrogenesis and reveal the manner in which the repair mechanisms function following renal injuries (e.g., from infections). Once this is clear, we will be in a position to translate our results into clinical medicine, screening for and potentially even preventing renal maldevelopment in utero. Ultimately, this research will expose the potential for gene therapies to overcome--or even prevent--kidney failure.
| Eddy, Allison A; López-Guisa, Jesús M; Okamura, Daryl M et al. (2012) Investigating mechanisms of chronic kidney disease in mouse models. Pediatr Nephrol 27:1233-47 |
| Zhang, Guoqiang; Kim, Heungsoo; Cai, Xiaohe et al. (2003) Urokinase receptor deficiency accelerates renal fibrosis in obstructive nephropathy. J Am Soc Nephrol 14:1254-71 |
