Molecular mechanism of
action of vitamin A in embryonic development, vitamin A and neuronal
survival and differentiation, retinoids in chemoprevention and
chemotherapy
Research in this
laboratory is focused on the molecular mechanism of action of vitamin A
and its metabolites. Much of the laboratory is devoted to understanding
how vitamin A functions during embryogenesis, with particular emphasis
on neural development. A second focal area is the use of retinoids
(natural or synthetic compounds related to A) in chemoprevention and
chemotherapy.
Embryonic development is disrupted both in
vitamin A deficiency and in excess. Using the rat embryo as a model, we
find that vitamin A deficiency during early embryogenesis leads to
defects in the patterning of the hindbrain, heart and skeleton; whereas
a deficiency imposed at later times leads to a host of anomalies in the
eye, kidney, diaphragm, heart, lung and urogenital system. Many of
these same developing systems are subject to malformation in retinoid
excess. Because retinoids are used therapeutically, embryotoxicity is a
real concern when using these compounds at pharmacological
concentrations. Before the therapeutic potential of retinoids can be
fully realized, it will be necessary to understand how vitamin A and
its metabolites function normally at the cellular and molecular level,
and how normal function is disrupted in toxicity.
Retinoids
act, in part, by binding to two families of nuclear retinoid receptors
(retinoic acid receptors, RARs; and retinoid-X receptors, RXRs). These
receptors function as ligand-activated transcription factors that
modulate gene transcription. The highest affinity ligand for the RAR is
all-trans retinoic acid (atRA). A major focus of the lab has been to
delineate the atRA-responsive genes whose expression is altered in
retinoid deficiency and/or excess and to establish how these changes
lead to an abnormal phenotype. Very recently, we have identified
several at RA-responsive genes by screening subtractive libraries from
retinoid treated and untreated cultures of human neuroblastoma cells
and primary cultures of embryonic sympathetic neurons. We are currently
studying the function of these genes in neuronal survival, cellular
differentiation and embryonic development.
We are also
devoting considerable effort to the development and study of retinoids
that may be useful in medical applications. Recent studies suggest that
a stable carbon linked analog of 4-hydroxyphenylretinamide as well as
several glucuronide retinoid conjugates are useful in chemoprevention
and chemotherapy, and have reduced toxicity relative to the parent
compounds. We are currently studying the mechanism of action of these
novel retinoids in cancer cell lines as well as in rats with DMBA
induced mammary tumors.
Photos
of Embryonic (day 6.5) chick sympathetic neurons cultured for 7 days
with nerve growth factor in the absence (left) or presence (right) of
the vitamin A metabolite, all-trans retinoic acid. Only neurons
receiving the vitamin A metabolite survive and extend neurites.