Trustees of Columbia University In The City of New York
Grant: $150,000 - National Institutes of Health - Sep. 11, 2009
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Award Description: Mild vitamin A deficiency is present in 5-7 million pregnant women worldwide, a condition that in animal models can result in sup-optimal organogenesis. Understanding the role of vitamin A during gestation is thus of great importance. Our studies of urogenital tract malformations induced by vitamin A deficiency may aide in understanding of the basis of these defects so that they can one day be treated or prevented.
Project Description: We propose to identify molecular pathways and cellular events that are required for formation of the bladder. The funding will allow us to obtain preliminary data relevant to urothelial differentiation. Retinoic acid (RA) is required for formation of most organs and tissues. RA is synthesized from vitamin A by retinol and retinaldehyde dehydrogenase. Once present in cells, RA binds to and activates RA-receptors, transcription factors belonging to the nuclear receptor superfamily. Inactivation of Raldh2, the major RA-synthesizing enzyme, results in abnormal bladder formation. Expression of a dominant negative RA-receptor in the bladder epithelium results in malformations that phenocopy those in Raldh2 mutants, indicating that RA is normally important in the bladder epithelium for bladder outgrowth and differentiation. Mutants expressing this dominant negative RA-receptor have abnormal urothelium. In wild type mice the urothelium consists of a basal, intermediate and umbrella cell that express uroplakins. We find the umbrella cell layer is absent in RA-dominant negative mutants, indicating that RA is normally required for differentiation of the umbrella cell layer and for maintaining barrier function in the bladder. Aim 1. How does vitamin A control urothelial formation? RA-signaling may be important for survival or differentiation of umbrella cell progenitors, or RA may act at a more basic level during the transformation of primitive endoderm to stratified urothelium. We will address these questions by performing immuno-histochemical analysis to define the cell types that are present in the bladder epithelium of RA-dominant negative mutants. We will examine if markers of the basal/intermediate cell layers are present and whether markers of early endoderm, the precursor of the bladder epithelium, have been down regulated.
Jobs Summary: N/A (Total jobs reported: 0)
Project Status: Not Started
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