1: ‘Hypoglycemia And Estrogen’
Model: Hypothalamic cell line
is a condition when the blood glucose level falls below normal levels.
Glucose is the main metabolic fuel of the brain. Recurrent episodes of
hypoglycemia can lead to seizures, coma, and even death. There is
evidence that estrogen, a steroid hormone, mainly produced by ovaries,
is required for the maintenance of glucose homeostasis.It
has been suggested that
estrogen affects cell viability, survival and proliferation and
regulates genes positively and negatively through intracellular
signaling of membrane receptors (e.g. G- protein, Ca++, cAMP,
etc) where the receptors are outside the nucleus in the cytoplasm or
the plasma membrane; the nongenomic pathway or membrane initiated
steroid signaling.. However, the molecular mechanism involving the
event is a subject of debate. We propose that estrogen exerts its
neuroprotective effect through the AKT-GSK3b signaling pathway since
our DNA microarray data suggest that AKT is downregulated in the
absence of glucose and in the presence of estrogen thre is an
upregulation promoting cell survival.
Does hypoglycemic injury trigger apoptosis in subpopulations of
hypothalamic neurons through specific death pathways? Is estrogen able
to provide protection against injury?
Is the neuroprotection of estrogen mediated through ERalpha or plasma
Are there caspase induced neuronal cell death?
Project 2: ‘Atrazine
as an Endocrine Disrupting Chemical’
Hypothalamic cell line/ Animals
is a widely used herbicide. It has been shown to
exhibit endocrine disrupting properties. A few studies demonstrate that
atrazine enhances estrogenic activity by stimulating aromatase, an
for converting testosterone to estrogen or by inhibiting
causes elevation of cAMP in cell lines which leads to increase in
production. Although evidence supports that atrazine affects the
pituitary gonadal axis, the specific molecular mechanism of
endocrine disruption is not completely understood.
1. How does the
atrazine-induced endocrine disruption affect the cellular mechanisms of
mouse hypothalamic cell lines?
2. How does the
atrazine-induced endocrine disruption affect the neonatal mice if
within 7 day of birth?
atrazine-induced endocrine disruption causing neuronal cell death lead
apoptotic cell death causing activation of caspases?
animals will be performed after
the IACUC approval
atrazine-induced endocrine disruption affect aromatase (CYP19) activity?
Project 3: ‘Effect of
estrogen and leptin in the estrous cycle of ob/ob and ovariectomized
ob/ob and Ovariectomized Mice
cycle is the recurring physiological changes occurring in the
endometrium of the uterus during the reproductive cycle. There is a
known impact of hormones like estrogen and leptin on the regulation of
the estrous cycle. Estrous cycle in mice is a 4-5 day cycle
characterized by proestros, estrous, metaestrous and diestrous, which
can be determined by the cell types obtained from the vaginal smear.
Analyzes of estrous cycle is an important tool as female mice are
considered to be an excellent model for the study of neuroendocrine
mechanism underlying a wide variety of normal functions and
pathophysiological conditions in human. Estrogen, a hormone secreted
mainly by the ovaries not only regulates the reproductive cycle but
also has a negative effect on food intake. Leptin, a hormone secreted
by the fat cells has an inhibitory effect on food intake. In this study
we tried to analyze the estrous cycle in relation with leptin and
estrogen levels in two mouse lines ob/ob and ovariectomized (OVX)
female mice, both of which are infertile, increased body weight, with
low or no estrogen but with contrasting leptin levels.
does that estrous cycle of ob/ob and OVX mouse vary among these animals?
there is any effect of
estrogen and leptin on the estrous cycle?
Project 4: ‘Regulation of
Feeding Circuits by Hormones and Neuropeptides and Menopause’.
Model: Ovariectomized mice and
Reproduction and feeding are
closely tied and are under the tight control of the
hypothalamic-pituitary axis. Menopause, a process that usually occurs
with age, there is a precipitous decline in circulating estrogen
levels, tends to be associated with an increased risk of obesity and
health risks that leads to increased insulin resistance, dyslipidemia,
high blood pressure, diabetes, heart disease and hypertension.
Estrogen, a hormone secreted by the ovaries and leptin an hormone
secreted by the fat cells is the main focus of this study. Our
hypothesis is that estrogen and estrogen receptor (ER) signaling
pathways play an important role in the regulation of feeding and energy
expenditure by interaction with hypothalamic neural pathways. Our
preliminary data indicate that ovariectomy in mice is associated with
an increase in the number of ER alpha (ER)-expressing cells in the
hypothalamic arcuate nucleus (ARH) compared to wild type females,
leading to changes in leptin receptor (LR) levels several months
following surgery. Moreover, leptin inhibits food intake by inhibiting
other proteins involved in the feeding circuit like neuropeptide Y
(NPY)/ agouti-related protein (AGRP) and proopiomelanocortin (POMC)(see
figure). It is thus possible that a decrease in circulating sex
steroids leads to an alteration in leptin responsiveness and there lies
a common signaling pathway for both leptin and estrogen. However, the
mechanisms of this interaction are largely unknown, yet a better
understanding of these circuits offers the potential for direct
therapeutic intervention to reduce obesity and the significant
morbidity that is associated with it in postmenopausal women. The objective of our proposal
is to define the role that estrogen, ER and neuropeptide signaling play
in the hypothalamus to influence energy homeostasis during menopause
using follicle-depleted and ovariectomized mice (OVX) as model systems.
This will be accomplished as follows:
1. How are
phenotypes (e.g. NPY/AGRP, POMC) of neurons in specific regions of the
hypothalamus that are ER positive, both in normal and
estrogen-deficient female mice regulated?
Determine whether the
neuropeptides (e.g. NPY/AGRP, POMC) colocalize with ER and the effect
of estrogen-deficiency on their gene expression in the ARH and whether
estrogen treatment alters the expression and circuits in any way?