| Joel M. Perrella,
MSc University of Toronto, Institute of Medical Sciences,
St. Michael’s Hospital
The Government
of Ontario/Pharmacia Canada Inc./Genesis Research Foundation/OBGYN
Graduate Scholarship in Science and Technology at the
University of Toronto, Faculty of Medicine.
(Scholarship:
Joel M Perrella, MSc University of Toronto, Institute
of Medical Sciences, St. Michael’s Hospital)
Thesis: “Mechanisms
of Neuronal Cell Death and Estrogen Protection”.
Alzheimer’s
disease (AD) is the most common cause of dementia, accounting
for 64% of all dementias. Presently 238,000 Canadians
over the age of 65 have AD and this number will rise
as the aging population increases. Studies have shown
that women are more susceptible to developing AD than
are men, and it has been postulated that the decrease
in estrogen levels during and following menopause may
play a significant role in this increased risk. Many
observational studies with women undergoing estrogen
replacement therapy have shown estrogen to be associated
with a possible preventative role against the development
of AD. In support of this, experimental evidence indicates
that estrogen can promote the formation of neural networks
in the brain and can also protect neuronal cells from
death caused by toxins that are believed to be involved
in the development of AD.
Joel
Perrella’s focus in the lab is on how estrogen modulates
signaling pathways in the neuron that lead to the prevention
of cellular death. One of these signaling pathways involves
a large influx of calcium into the neuron, which has
the ability to activate key enzymes that initiate the
process of cellular death. Initially Mr. Perrella has
investigated how estrogen regulates calcium influx into
the neuron to determine if calcium modulation is one
mechanism by which estrogen exerts its neuroprotective
effects. As part of this work he will compare different
estrogenic components of the most widely prescribed
estrogen replacement therapy to determine if some estrogen
components affect calcium influx to a greater degree
than other components. In addition to these studies
he will also look at how estrogen exerts this modulation,
whether it is directly or via an interaction with its
cellular and membrane receptors.
It is
researcher Joel Perrella’s hope that this study will
contribute to an understanding of the mechanisms responsible
for the cellular death observed in disease states such
as AD. More importantly, this research may provide insights
into how to stop or delay the onset of neurodegenerative
diseases. Paramount to these goals is the potential
to develop a novel therapeutic alternative for women
and men, at risk for developing Alzheimer’s disease,
in the form of an estrogenic derivative that does not
possess the negative side- effects typically associated
with estrogen use.
Government
of Ontario/R. Howard Webster Foundation/Genesis Research
Foundation/Physiology Graduate Scholarship in Science
and Technology at the University of Toronto.
(Scholarship:
Shathiya Hulandavelu, Mt. Sinai Hospital, Department
of Physiology)
Thesis: "Role
of Endothelial-Derived Nitric Oxide in Maternal Cardiovascular
Changes During Pregnacy."
To maintain
an ideal environment in both the maternal and fetal
compartments during pregnancy, the mother undergoes
various adaptations including a marked, early decrease
in peripheral vascular resistance. This decrease is
believed to be the primary event leading to an increase
in cardiac output, blood volume and a decrease in blood
pressure during normal human pregnancy. The mechanisms
mediating these changes are poorly understood but important
because their failure likely underlies two of the most
common and serious disorders of human pregnancy, preeclampsia
(~7%) and fetal growth restriction (~10%).
The main
mediator of the primary peripheral vasodilation in pregnancy
is unknown, but the vasodilator nitric oxide (NO) is
thought to play a vital role because considerable amount
of data in humans and rats suggests that basal NO production
is elevated during pregnancy. Also inhibition of NOS
isoforms has shown to lead to preeclamptic symptoms
including hypertension. Effects are likely mediated
by endothelial-derived NO (eNOS) but there are no specific
eNOS inhibitors available. Therefore, now with the availability
of eNOS knockout (-/-) mice, the obligatory role of
eNOS in mediating the cardiovascular changes seen during
pregnancy can be studied. Shathiyah has shown from her
initial studies that the eNOS pathway is not essential
for vasodilation and increased cardiac output during
early pregnancy, but plays a critical role in late gestational
changes. Thus, Shathiyah will now focus to define the
mechanisms involved in mediating the cardiac output
changes in early and late pregnancy in normal and eNOS
-/- mice by looking at changes in peripheral vascular
resistance and the effects of volume expansion. Furthermore,
she will examine the expression of NOS isoforms during
pregnancy to gain new basic information on the regulation
of eNOS expression, NOS activity and the role of NO
in pregnancy.
These
studies will enhance our understanding of the mechanisms
controlling the normal cardiovascular changes during
pregnancy, and examine the role played by nitric oxide
in mediating these changes. Also, this work will establish
methodology and background information required to fully
exploit other genetically modified mouse models. Ultimately,
this can lead to improved treatments for problems such
as preeclampsia and intrauterine growth restriction.
|
