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Name:
Institute:
Department:
Email:
Website:
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Dr. Nirmal Charan
Boise VA Medical Center
Nirmal.Charan@med.va.gov
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Research:
The
main focus of our research is studying the airway circulation in health and
disease. At the present time, we are investigating if drugs that are given
by inhalation are delivered to the bronchial smooth muscles by the bronchial
circulation. The studies are being conducted in an anesthetized sheep
model.
Summer Project:
The fellow assigned to our laboratory will help us in conducting the above
mentioned research project. During this period, he/she will learn the
procedure of anesthetizing sheep, technical aspects of performing surgery,
collection physiological data, and statistical analysis of these data.
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Name:
Institute:
Department:
Email:
Website:
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Dr. Barry Cusack
Boise VA Medical Center
barry.cusack@med.va.gov
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Research:
We study the
pharmacokinetics of anthracycline anti-cancer drugs in relation to age in a
rat model. We have observed that the plasma and heart levels of
anthracyclines, such as doxorubicin and daunorubicin and their alcohol
metabolites, are elevated in older compared with young adult rats.
We now are
studying mechanisms to explain these observations. These include assay of
expression of anthracycline reductase and its activity in heart tissue in
relation to age in the rat. We also are examining expression and activity
of P-glycoprotein, an important transmembrane transporter in the heart in
relation to age. These studies have been extended to include MRP-1, another
transporter of anthracyclines across cell membranes.
Summer Project:
1.
To assist in developing cell culture models from heart in the rat. These
could then be used to examine cell membrane drug transport.
2. To study gene
expression of P-gp and MRP-1 in tissues including heart, liver and kidney in
rats of different age.
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Name:
Institute:
Department:
Email:
Website:
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Dr. Herve Gambliel
herve.gambliel@med.va.gov
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Research:
My research
is focused on understanding the molecular pathways involved in
anthracycline-related heart disease. Anthracycline drugs are widely
used in chemotherapy to combat cancer but unfortunately often also lead to
oxidative stress-related impairments in cardiac contractility. We have
used a structure-activity approach using anthracycline analogs that are
either unable to redox cycle (5-imino-doxorubicin), or to form a primary
cardiotoxic metabolite (doxorubicinol), or both (C-13
deoxy-5-imino-doxorubicin) to try to understand the contribution of the
pathogenesis of cardiac lesions. Our results indicate that decreased
expression and impaired function of the sarcoplasmic reticulum calcium
release channel (RYR2) represents an important facet of disease development.
We are presently examining more closely the effect(s) that these drugs exert
on RYR2 and its accessory proteins. These studies should provide valuable
insights to optimize strategies to minimize the cardiotoxicity of
anthracyclines and enhance their effectiveness as chemotherapeutic agents.
Summer
Project:
We would like to use a
small interfering RNA (SiRNA) strategy to selectively decrease expression of
the key accessory protein triadin to modulate the gating of the ryanodine
receptor. An analysis of cardiomyocytes expressing decreased level of this
protein and treated with or without our anthracycline analogs should help us
better understand the mechanisms underlying the effects of these drugs on
calcium release. A possible summer project then would be to make cDNA
constructs expressing triadin SiRNAs under an inducible promoter, validating
the decrease in expression of that protein and if time allows measure its
effect on the open state of the ryanodine receptor (ryanodine binding
assays).
We are also interested
in the development of new biomarkers for detecting anthracycline
cardiotoxicity. This project would involve detecting the levels of several
candidate circulating peptides in plasma that have potential clinical value
as indicator of cardiotoxicity. We have developed methodology to recover
peptides but need to develop improved detection schemes to simultaneously
detect several of these peptides.
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