Title: Development Of Cushings Syndrome In CorticotropinReleasing Factor Transgenic Mice
1Development Of Cushings Syndrome In
Corticotropin-Releasing Factor Transgenic Mice
- Stenzel-Poore, M.P., V.A. Cameron, J. Vaughan,
P.E. Sawchenko, and W. Vale. 1992. Development of
Cushings Syndrome in Corticotropin-Releasing
Factor Transgenic Mice. Endocrinology 130
3378-3386. - http//access.barry.edu2138/cgi/reprint/130/6/337
8.pdf
2CONTENTS
- Background
- Hypothalamic/pituitary axis in health
- What happens when axis is perturbed
- Cushings Syndrome (Definition)
- Signs/Symptoms
- Diagnosis
- Treatments
- Primary Source Article
- -Objective
- -Data
- Conclusion
- References
3BACKGROUND
- Cushings Syndrome (1932)
- Harvey William Cushing
- Cushings Syndrome affects more women than men
- Characteristic type of obesity of the face, neck,
and trunk
4The adrenal cortex is under the control of the
pituitary gland
- IN HEALTH
- Releasing hormone from the hypothalamus.
- ACTH production from the anterior pituitary.
- Glucocorticoids from the adrenal cortex
5CUSHINGS SYNDROME
- The hypothalamic/pituitary axis is disturbed
- Hormonal disorder caused by chronic
glucocorticoid excess - Disorder in which the body tissue is exposed to
excess levels of the hormone cortisol - Most common type of cushings syndrome is caused
by exposure to high levels of ACTH
6SIGNS/SYMPTOMS
- Facial obesity (Moon Face)
- Fatty swellings (Buffalo Hump)
- Weight gain w/ rounding of the face
- Increased fat in the neck
- Bruising of the skin
- Muscle weakness
- Osteoporosis
- High blood sugar
- Diabetes
- High blood pressure
7SIGNS/SYMPTOMS
8SIGNS/SYMPTOMS
9DIAGNOSIS
- Biochemical laboratory test
- Dexamethasone suppression test (DST)
- ACTH stimulation test
10TREATMENTS
- Bromocriptine Mesylate
- 5 mg capsule
- Dopamine agonist
- Known to be the original drug to treat this
disorder - Decreases ACTH cortisol levels
11POSSIBLE SIDE EFFECTS
- Mild nausea
- Vomiting
- Abdominal cramps
- Diarrhea or constipation
- Dizziness or drowsiness
- Dry mouth
- Nasal stufness
- Headache
12- Development Of Cushings Syndrome In
Corticotropin-Releasing Factor Transgenic Mice. - Stenzel-Poore, M.P., V.A. Cameron, J. Vaughan,
P.E. Sawchenko, and W. Vale. 1992. Development of
Cushings Syndrome in Corticotropin-Releasing
factor Transgenic Mice. Endocrinology 130
3378-3386.
13What Is CRF?
- Corticotropin-Releasing Factor (CRF) is a
41-residue hypothalamic peptide - CRF is synthesized in the hypothalamus and
regulates adrenocorticotropic hormone (ACTH)
secretion glucocorticoid production from the
posterior pituitary - CRF plays a major role in behavioral responses to
stress and acts as a neurotransmitter in
extra-hypothalamic systems - The overproduction of CRF leads to disorders such
as depression, anorexia nervosa, and Cushings
Syndrome
14Objective
- To examine the endocrine and behavioral effects
of chronic CRF excess that leads to Cushings
Syndrome - To develop a transgenic mouse model that
overexpress CRF of chronic pituitary-adrenal
activation
15Rationale
- CRF transgenic animals display endocrine
abnormalities such as high plasma levels of ACTH
constant elevated levels of circulating
glucocorticoid in the hypothalamic-pituitary
adrenal (HPA) axis - The founder animals with high levels of
circulating CRF show truncal obesity with large
adipose deposits, muscle wasting, bilateral
symmetric hair loss, and abnormal transparent skin
16Generation of MT-CRF Mice With Cushings Syndrome
- The transgenic male animal on the left expresses
high levels of CRF with elevated ACTH release and
increase corticosterone production and shows
features of Cushings Syndrome with decreased
linear growth, bilateral hair loss, and increased
fat accumulation - The non-transgenic control littermate on the
right shows no signs of Cushings Syndrome
17Generation of MT-CRF Mice With Cushings Syndrome
18Generation of MT-CRF Mice With Cushings Syndrome
- Murine Metallothionein-1 (m MT-1) gene promoter
was used to avoid feedback regulation of the CRF
transgene expression - Metallothionein-CRF (MT-CRF) gene extends from
the Asp718 site in the 5 untranslated region to
the EcoRI site in the 3 untranslated region
19Generation of MT-CRF Mice With Cushings Syndrome
20ACTH and Corticosterone Levels in CRF Transgenic
Mice
- Basal levels of ACTH and Corticosterone were
measured in serum obtained from offspring derived
from a single family - ACTH values were 5-fold greater than control
nontransgenic animals. This increase can
stimulate the secretion of corticosterone from
the adrenal glands - In transgenic offspring, corticosterone levels
were 10-fold greater than the baseline control
21ACTH and Corticosterone Levels in CRF Transgenic
Mice
22CRF gene expression in peripheral tissues of
MT-CRF transgenic mice
- Stenzel-Poore and colleagues were able to
determine the tissue distribution of the CRF gene
expression because the transgenic animals
displayed high plasma ACTH levels without an
increase in plasma CRF
23CRF gene expression in peripheral tissues of
MT-CRF transgenic mice
24CRF gene expression in peripheral tissues of
MT-CRF transgenic mice
25CRF gene expression in peripheral tissues of
MT-CRF transgenic mice
26CRF in transgenic mouse brains using a rat CRF
cRNA probe
27CRF in transgenic mouse brains using a rat CRF
cRNA probe
28CRF in transgenic mouse brains using a rat CRF
cRNA probe
29- A transgene-specific oligonucleotide probe was
used to verify the expression of the CRF
transgene in regions where high levels of CRF
expression were observed - This transgene-specific oligonucleotide probe
exposed a hybridization pattern that was similar
to the rat gene CRF probe - In other words, the regions of heightened
expression were due to the transgene
30Transgene-specific oligonucleotide in transgenic
mouse brain
31Transgene-specific oligonucleotide in transgenic
mouse brain
32Conclusion
- Cushings Syndrome is due to chronic
glucocorticoid excess and exposure to high levels
of ACTH - CRF is released in the hypothalamus as a
neuromodulator, regulates ACTH secretion, and
plays a major role in stress responses
33References
- Stenzel-Poore, M.P., V.A. Cameron, J. Vaughan,
P.E. sawchenko, and W. Vale. 1992. Development of
Cushings Syndrome in Corticotropin-Releasing
Factor transgenic Mice. Endocrinology 130
3378-3386. - Orth, D.N. 1992. Cushings Syndrome. Medical
Progress 332 791-803. - Shaw, G. Spring 2003. Lecture Notes.
Endocrinology.