| Government of Ontario/R. Howard Webster Foundation/Genesis Research
Foundation/Physiology Graduate Scholarship in Science and Technology at the University of Toronto 2006/2007
Thesis: Placental Multidrug Resistance: Glucocorticoid Interactions
Multidrug resistance phosphoglycoprotein
(Mdr1/P-gp) belongs to a superfamily of ATP-dependent
transporters shown to actively transport a wide range
of compounds including antiretroviral HIV protease inhibitors,
cardiac glycosides, analgesics as well as exogenous
and endogenous steroids. The human multidrug resistance
gene (MDR1) was first discovered in tumor derived
cells, where it was shown to be involved in the development
of resistance to chemotherapeutic agents. Subsequently,
multidrug resistance genes (mdr1a and mdr1b)
have been identified in the mouse and together are believed
to functionally resemble MDR1.
More recently, Mdr1/P-gp
has been identified in a number of normal tissues including
the intestines, kidney, liver and adrenal where it has
been shown to play an important role in limiting absorption
and/or facilitating excretion of a wide range of substrates.
Tissues with specialized barrier functions such as the
blood-brain, blood-testes and blood-placental barriers
also express Mdr1/P-gp. Information pertaining
to Mdr1/P-gp’s regulation and functional
significance in the placenta is minimal.
In most mammals (including human)
maternal plasma GC concentrations are 2-10 fold higher
than those found in fetal circulation. Fetal protection
from high maternal GCs is critical to fetal development.
Fetal exposure to GCs of maternal origin is regulated
by the placenta. One mechanism controlling fetal exposure
to maternally derived GCs is placental 11ß-hydroxysteroid
dehydrogenase enzyme type 2 (11ß-HSD2). Recently,
the functional importance of Mdr1/P-gp in preventing
GC entry into specialized barrier tissues has been demonstrated,
such that in the brains of Mdr1/P-gp knockout
(KO) animals, a 2-fold increase in GC transfer was observed
as compared to wild-type. Similar mechanisms likely
operate in other specialized barrier tissues such as
the placenta.
We have recently
shown high levels Mdr1/P-gp in the syncitial
layers of the placenta at mid-gestation, followed by
a dramatic decrease in late gestation. Further, our
transfer studies have established the importance of
placental Mdr1/P-gp in limiting drug transfer
of Mdr1/P-gp specific substrates to the developing
fetus. These studies also demonstrated a close correlation
between placental expression and Mdr1/P-gp
function. However, the role of placental Mdr1/P-gp
in the prevention of transplacental GC transfer has
not been investigated. We now propose a novel model
whereby placental Mdr1/P-gp acts in concert
with 11ß-HSD2 to protect the fetus from maternally
derived GCs. The focus of my doctoral studies is: 1)
to determine the role of placental Mdr1/P-gp
in fetal protection against maternally derived glucocorticoids
(GCs) and 2) to determine
whether GCs can modulate expression and/or function
of placental Mdr1/P-gp.
Hypothesis:
1) Placental Mdr1/P-gp plays a critical role
in protecting the developing fetus from maternally derived
GCs. 2) GCs regulate the expression and function of
placental Mdr1/P-gp.
Given the potential
protective effects of placental Mdr1/P-gp,
it is imperative that we understand its function and
regulation during pregnancy. This new knowledge will
enable the development of improved strategies for fetal
protection against the entry of excess GC as well as
other drugs and potential teratogens during inappropriate
time ‘windows’ of development.
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