We are proposing to use tracer kinetic methodologies to ask questions about the factors and processes that are important for accumulating and maintaining all-trans retinoic acid within tissues. The general question we propose to ask is: How do tissues in the intact animal acquire and maintain the all-trans retinoic acid need for regulating building on and further developing experimental and analytical methodologies and kinetic modeling approaches for the study of retinoic acid metabolism which we successfully used in the rat model. All of the studies which we are proposing in the project are focused on exploring and/or confirming one hypothesis regarding retinoid transport and metabolism. This hypothesis is that cells and tissues regulate intracellular retinoic acid concentrations and that all retinoid homeostatic mechanisms which the body are focused on maintaining intracellular retinoic acid concentrations. We believe that this is the cardinal imperative for regulating all retinoid transport and metabolism within the body. Our studies consist of four Specific Aims. First, we propose to validate the tracer kinetic methodologies which we developed and used in the rat model for the mouse. Then, using different strains of induced mutant mice which either have markedly different patterns and/or levels of circulating retinol, retinyl esters and retinoic acid or which lack a protein proposed to be importantly involved in retinoic acid synthesis within cells, we propose to employ these tracer kinetic approaches to ask how these differences influence retinoic acid turnover and metabolism in plasma and tissues of the mutant mice. These studies will shed light on our hypothesis that within the body the homeostatic mechanisms for regulating retinoid transport and metabolism are geared towards maintaining constant intracellular retinoic acid concentrations.

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Columbia University (N.Y.)
New York
United States
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Chung, Sanny S W; Wang, Xiangyuan; Wolgemuth, Debra J (2009) Expression of retinoic acid receptor alpha in the germline is essential for proper cellular association and spermiogenesis during spermatogenesis. Development 136:2091-100
Shang, Enyuan; Salazar, Glicella; Crowley, Thomas E et al. (2004) Identification of unique, differentiation stage-specific patterns of expression of the bromodomain-containing genes Brd2, Brd3, Brd4, and Brdt in the mouse testis. Gene Expr Patterns 4:513-9
Crowley, ThomasE; Brunori, Michele; Rhee, Kunsoo et al. (2004) Change in nuclear-cytoplasmic localization of a double-bromodomain protein during proliferation and differentiation of mouse spinal cord and dorsal root ganglia. Brain Res Dev Brain Res 149:93-101
Chung, S S W; Wolgemuth, D J (2004) Role of retinoid signaling in the regulation of spermatogenesis. Cytogenet Genome Res 105:189-202
Chung, Sanny S W; Cuzin, Francois; Rassoulzadegan, Minoo et al. (2004) Primary spermatocyte-specific Cre recombinase activity in transgenic mice. Transgenic Res 13:289-94
Chung, Sanny S W; Sung, Wengkong; Wang, Xiangyuan et al. (2004) Retinoic acid receptor alpha is required for synchronization of spermatogenic cycles and its absence results in progressive breakdown of the spermatogenic process. Dev Dyn 230:754-66
Paik, Jisun; Blaner, William S; Sommer, Karen M et al. (2003) Retinoids, retinoic acid receptors, and breast cancer. Cancer Invest 21:304-12
Crowley, Thomas E; Kaine, Emily M; Yoshida, Manabu et al. (2002) Reproductive cycle regulation of nuclear import, euchromatic localization, and association with components of Pol II mediator of a mammalian double-bromodomain protein. Mol Endocrinol 16:1727-37
Shang, Enyuan; Lai, Katherine; Packer, Alan I et al. (2002) Targeted disruption of the mouse cis-retinol dehydrogenase gene: visual and nonvisual functions. J Lipid Res 43:590-7
Mendelsohn, C; Batourina, E; Fung, S et al. (1999) Stromal cells mediate retinoid-dependent functions essential for renal development. Development 126:1139-48