Antonella Racano
|
Government of Ontario/R. Howard Webster Foundation/Genesis Research Foundation/Physiology Graduate Scholarship in Science and Technology at the University of Toronto 2008/2009
Thesis: The Role of Factor Inhibiting HIF-1 (FIH-1) in Normal and Pathological Human Placentae
The human placenta mediates the physiological
exchange of gas, nutrients, and waste between mother
and fetus. In vitro studies have shown oxygen
to be a key regulator of trophoblast differentiation
and, thus, of placental development. Early placentation
occurs in a relatively hypoxic environment, which supports
proliferation of the trophoblast cells. Around 10-12
weeks of gestation, when the placenta opens to the maternal
circulation, oxygen levels rapidly increase and promote
trophoblast cell invasion of the uterine wall. Impairment
of these key cellular events during early placentation,
as a result of altered oxygenation and/or impaired oxygen
sensing by the trophoblast cells, is thought to have
implications in pregnancy-related disorders, such as
Preeclampsia (PE) and Intrauterine Growth Restriction
(IUGR). PE and IUGR, which are characterized by improper
placental development and placental hypoxia, affect
7%-10% of all pregnancies and remain the most common
cause of fetal and maternal mortality and morbidity;
their etiologies, however, remain an enigma.
In most mammalian systems, Hypoxia
Inducible Factor-1 (HIF-1) is the major player involved
in sensing low levels of cellular oxygen and eliciting
the appropriate adaptive responses. HIF-1 is a transcription
factor composed of an inducible -subunit and a constitutive
-subunit. Under hypoxic conditions, HIF-1 is stable
and promotes the transcription of a variety of genes
involved in erythropoiesis, angiogenesis, and glycolysis.
Under normoxic conditions, HIF-1is targeted for proteasomal
degradation, following proline hydroxylation, by the
(oxygen-dependent) prolyl hydroxylases domain (PHD)
enzymes. Additionally, in normoxia, Factor Inhibiting
HIF-1 (FIH-1), an oxygen-dependent asparginyl hydroxylase,
specifically targets and hydroxylates the Asn803 residue
located in the C-terminal transactivation domain (C-TAD)
of HIF-1. This hydroxylation event, in turn, prevents
HIF-1 from recruiting the transcriptional coactivator
CBP/p300, and thereby represses its transcriptional
activity. Moreover, it has recently been shown that
FIH-1 selectively controls the expression of a variety
of HIF-1 target genes, further highlighting its intricate
role in fine-tuning the HIF-1 machinery.
While numerous studies have investigated specific aspects of HIF-1 regulation, little is known about the mechanisms by which HIF-1 transcriptional activity is regulated in both hypoxia and normoxia. We have recently demonstrated that during human placental development, HIF-1 stability is spatially and temporally regulated by the PHDs and that HIF-1 expression is upregulated in PE. The role of FIH-1 in human placental development and in placental pathologies has never been considered.
As such, the focus of my graduate studies will be to establish the spatial and temporal expression of FIH-1 throughout human placental development and in placental pathologies; to investigate the role of FIH-1 in regulating downstream HIF-1 target genes in the human placenta; and to determine the upstream regulation of FIH-1.
Hypothesis: FIH-1
plays an important role in regulating the expression
of HIF-1 target genes during human placental development.
Consequently, disruption of FIH-1 expression and function
during early placentation contributes to aberrant expression
of HIF-1-dependent genes and, in turn, may predispose
the pregnancies to PE and/or IUGR.
|
