The ability of tissues to respond to vitamin A is affected by three factors: delivery of vitamin A, predominantly as retinol, to the tissues from the circulation; uptake of vitamin A from circulating pools and subsequent metabolism into biologically active forms within the tissue; and the presence of functional retinoic acid and retinoid receptors that mediate the genomic response, or the other response to vitamin A metabolites. In this project I am proposing a genetic approach to determine the importance of cyclical CRBP expression and of retinoid status in sustaining normal cervical squamous metaplasia. These experiments will utilize mice in which either the CRBP or RARalpha genes have been disrupted by homologous recombination, and mice in which CRBP is constitutively expressed in basal and suprabasal keratinocytes. The proposed experiments are divided into two complimentary parts.
In Aim 1 studies are proposed to establish the effects of dysregulated CRBP expression and of vitamin A insufficiency on the differentiation of the cervical epithelium.
In Aim 2 experiments are proposed that will use cultured cervical epithelial cells isolated from CRBP+/+ and CRBP-/- mice to establish the effect of CRBP expression on differentiation of cultured CECs, on retinol uptake and metabolism in CECs, and on RAR function.
The Aims of this Project are:
Aim 1. Determine if CRBP modulates in vivo retinoid status in the rodent cervix.
Aim 2. Determine if CRBP alters retinol uptake and metabolism, or retinol regulation of cultured cervical epithelial cell differentiation. Although these experiments focus on the role of RBP in the biology of the cervical epithelium, the insights gained should be applicable to other tissues in which vitamin A status must be dynamically regulated.
|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|