| Vitamin
A (retinol) and its analogs, retinoids, are essential for many critical
life processes including vision, reproduction, cellular
differentiation,
bone development, and apoptosis. All-trans-retinoic acid
and
its isomer 9-cis-retinoic acid are biologically active
metabolites
of retinol. These compounds function as ligands for retinoid
receptors,
which mediate gene expression and control cellular processes throughout
an organism’s lifetime. All-trans-retinoic acid (t-RA) and
9-cis-retinoic acid (9-cis-RA) activate retinoic acid receptors (RAR α,
β, and γ) and retinoid X receptors (RXR α, β, and γ). These retinoids
act as ligand-dependent transcription factors with t-RA activating
RARs, while 9-cis-RA serves as a pan-agonist for RARs and RXRs.
These receptor complexes act as heterodimers or homodimers binding to
specific retinoid response elements, RARE and RXRE, in the promoter of
target genes. RXRs are promiscuous receptors forming heterodimers
with other ligand-dependent members of the nuclear receptor family
including thyroid hormone, vitamin D receptors, and more recently
peroxisome proliferator activated receptor gamma (PPARγ).
Our lab is interested in how retinoids establish and
maintain proper immunity by mediating immunological functions such as
differentiation, adhesion, proliferation, and transmigration of
leukocytes. Recently, retinoids and PPAR gamma agonists, such as
those belonging to the thiazolidinedione class (troglitazone,
roglitazone, and pioglitazone) have become more of a focus in regards
to their roles in regulation of inflammation and immune
responses. Cell adhesion is an integral aspect of immunity which
fascilitates the movement of white blood cells from the vascular to the
tissue surrounding them. Cell surface adhesion molecules, such as
integrins, mediate cell-cell and cell-matrix interactions and are
essential for maintaining cell homeostasis. Integrins, a family
of transmembrane heterodimeric receptors consisting of non-covalently
linked α and β subunits, are considered to be the principle receptors
involved in attachment to the extracellular matrix. Integrin
engagement with their counter ligands leads to signaling processes that
are critical for cellular proliferation and migration. The
α5β1 integrins are fibronectin receptors with the arg-gly-asp (RGD)
sequence in the FNIII domain 10 being the crucial attachment site for
α5β1. Interestingly, both retinoids and thiazolidinediones have
been implicated in altering integrins and their
counter-receptors. Retinoids influence expression of classical
integrin ligands and modulate integrin expression. One of
the projects in my lab is to detemine which retinoid receptors may be
responsible for regulating cellular adhesion and proliferation in human
immune cells.
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