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February 1998
Volume 62 |
Number 2
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FAER REPORT
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| FAER Honors Recent
Award Recipients, Part 2 |
"The Board of Directors for the Foundation for Anesthesia Education
and Research (FAER) is pleased to announce the latest recipients
of the FAER awards (NEWSLETTER, January
and February 1998). FAER is grateful to and appreciative of
the generous support and contributions from ASA, its individual
members, component societies, subspecialty societies and corporations
which makes the funding of these researchers possible. FAER is
particularly thankful to the following societies and corporations
that have co-sponsored the awards being announced in this article:
American Society of Critical Care Anesthesiologists (ASCCA), Association
of University Anesthesiologists (AUA), American Society of Regional
Anesthesia (ASRA), Society for Ambulatory Anesthesia (SAMBA),
Society of Cardiovascular Anesthesiologists (SCA), Society for
Education in Anesthesia (SEA), Society of Neurosurgical Anesthesia
and Critical Care (SNACC); Abbott Laboratories, Astra Pharmaceutical
Products, Inc., Glaxo Wellcome, Inc., Hewlett-Packard Corporation,
Mallinckrodt Medical, Inc., Roche Pharmaceuticals, SIMS, and Zeneca
Pharmaceuticals, Inc. FAER also wants to thank the applicants
for their interest in the awards, research, and for submitting
such high quality proposals. The project summaries were provided
by the recipients.
Research Starter Grant Recipients:
David J. Clark, M.D., Ph.D., University of Washington,
Seattle, Washington, "Regulation of Expression of Potassium Ion
Channels by Opiates"
Potassium (K) channels underlie the regulation
of a variety of important physiological processes. Importantly,
opiates acting through specific receptors activate K-channels,
thus causing hyperpolarization of neurons and decreases in neurotransmitter
release in many areas of the nervous system. To this point much
of the effort directed at understanding the mechanisms of opiate
tolerance on the molecular level has focused on changes in opiate
receptor expression. Left unexplored are changes in expression
of K-channels which comprise the effector portion of the opiate-mediated
signaling pathway. We hypothesize then that certain K-channels
may have their expression regulated by chronic exposure to opiates
in the spinal cord and dorsal root ganglia. These experiments
investigate this hypothesis in a mouse model of opiate tolerance
using techniques to measure mRNA and protein levels. It is hoped
that the results of these experiments will suggest new avenues
of investigation regarding the prevention and treatment of opiate
tolerance.
Scott Mittman, M.D., Ph.D., Johns Hopkins University
School of Medicine, Baltimore, Maryland, "Selective Expression
of Na+ Channel a-subunit Isoforms on Nociceptors"
Agents capable of selectively blocking the
voltage-gated sodium channels of nociceptors (sensory neurons
mediating pain) would dramatically improve the treatment of
perioperative, obstetric and chronic pain. Such agents would
attenuate nociceptive neurotransmission without the problems
associated with current local anesthetics, seizures, cardiotoxicity,
permanent nerve dysfunction and blockade of other peripheral
nerve modalities. Development of such agents rests on the hypothesis
that nociceptors differ from other excitable cells in the sodium
channels expressed on their membranes. This study will directly
test this hypothesis by analyzing the sodium channel alpha-subunit
mRNA transcripts found in single, anatomically and physiologically
characterized peripheral neurons (nociceptors, non-nociceptors,
motor neurons, sympathetic neurons). If certain types of sodium
channels are indeed selectively expressed on nociceptors, these
channel types will be likely targets for the development of
improved agents for the treatment of pain.
David M. Roth, M.D., Ph.D., University of California,
San Diego, California, "Increased Adenylylcyclase Expression and
Cardiac Function"
Congestive heart failure (CHF) is the most significant
predictor of perioperative cardiac morbidity. Alterations in adrenergic
responsiveness in CHF are the focus of extensive research. Defects
in myocardial adrenergic signaling occur in patients and animal
models of CHF including the down regulation of cardiac adenylylcyclase
isoform VI (ACVI). The genetic overexpression of cardiac
ACVI provides a unique target for investigation and
therapeutic intervention. I will test the hypothesis that transgenic
mice overexpressing cardiac ACVI will demonstrate increased
AC activity and increased cardiac contractile function. Hearts
will be isolated from mice overexpressing AC ACVI.
AC activity will be studied in vitro. Cardiac function will be
determined in vivo using left ventricular pressure monitoring
and echocardiography and ex vivo in an isolated preparation. This
research provides important information concerning the role of
AC in normal cardiac function and supports future investigations
into the use of ACVI overexpression as a novel treatment
for heart failure.
Anesthesiology Research Fellowship Recipient:
Andrew Patterson, M.D., Stanford University School of
Medicine, Stanford, California, "The Beneficial Role of ß-Adrenergic
Receptor Blocking Agents in the Treatment of Congestive Heart
Failure: Examination of the Molecular Mechanisms of Action"
We will investigate the molecular mechanisms
by which drugs known as "ß-blockers" benefit patients
with congestive heart failure (CHF). CHF is associated with
increased epinephrine and norepinephrine concentrations. Elevated
levels of these catecholamines are known to induce a reduction
in ß1-adrenergic receptor number (downregulation)
and an uncoupling of ß2-adrenergic receptors
from their signal transduction cascades (desensitization). These
phenomena are associated with diminished cardiac function. ß-blockers
are believed to benefit CHF patients inhibiting downregulation
and desensitization. We hypothesize that, in addition to preventing
downregulation and desensitization, some ß-blockers help
the heart by weakly activating ß-receptors (partial agonism)
or by blocking a1-adrenergic receptors (reducing
resistance against which the heart must pump blood). We will
test several ß-blockers for partial agonist properties
using ß-receptor/Gs fusion proteins sensitive
enough to identify partial agonist activity. We will also use
adrenergic receptor knockout technology to identify receptors
necessary for the activity of several different ß-blockers.
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