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.
