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May 1996
Volume 60 |
Number 5
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FAER REPORT
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| FAER Announces
1996 Young Investigator Award Recipients |
The Board of Directors of the Foundation for Anesthesia Education
and Research (FAER) is pleased to announce the recipients of the
1996 Young Investigator Awards. Thirty-seven applications for
this program were received and reviewed. Seven awards were made,
but funding of all grants deemed worthy of such support by the
ASA Committee on Research (FAER Study Section) was not possible.
Funding will be made to the investigators' institutions.
The following information regarding FAER Young Investigator Awards
identifies the sponsors who have generously contributed to the
support of these grants. The descriptions of the projects have
been provided by the investigators.
Paul M. Chetham, M.D., University of Colorado, Denver, Colorado,
FAER/Society of Cardiovascular Anesthesiologists Young Investigator:
"Regulation of Ischemia-Reperfusion Pulmonary Edema by Endothelial
Cell Phosphatases"
Lung transplantation is the only therapeutic option for many patients
with end-stage lung disease. After a patient undergoes this type
of procedure, it is common for the donor lung to accumulate fluid
referred to as "pulmonary edema." Pulmonary edema and
its treatment can lead to potentially life-threatening complications.
We have designed a rat model to study this phenomenon known as
"Ischemia-Reperfusion Edema." The phosphorylation status
of lung capillary endothelial cell myosin light chain (MLC20)
is important for the regulation of barrier function. We hypothesize
that ischemia-reperfusion edema may represent a disturbance of
MLC20 phosphorylation status via endothelial cell phosphatases
and have proposed studies to test this idea. A better understanding
of these mechanisms may lead to improved organ preservation techniques
and ultimately decrease complications associated with lung transplantation.
Neil E. Farber, M.D., Ph.D., Medical College of Wisconsin,
Milwaukee, Wisconsin, FAER/ Ohmeda Pharmaceutical Products Young
Investigator: "The Role of Nitric Oxide in Modulating Volatile
Anesthetic-Induced Actions on Intracerebral Microvessels"
The proposed studies will examine the vasodilation of intracerebral
resistance vessels by volatile anesthetics and will test the hypothesis
that cerebrovascular responses to volatile anesthetic agents are
associated with local neuronal activity and that this coupling
is mediated by nitric oxide. Cerebral blood flow regulation is
precise and responsive to the high energy demands of active neurons.
Nitric oxide is an endogenous vasodilator produced in endothelium,
neurons and astrocytes, and there is growing evidence that nitric
oxide may mediate the neurogenic regulation of cerebral blood
flow. These studies will determine whether intracerebral microvessel
diameter and local neuronal function differ in response to volatile
anesthetic administration before and after inhibition of nitric
oxide or selective inhibition of brain nitric oxide synthase and
after exogenous administration of a nitric oxide donor. Videomicroscopy
and spontaneous extracellular neuronal activity will be examined
in a novel rat brain slice preparation in which microvessels remain
embedded within their natural microenvironment. These investigations
will enhance our understanding of the mechanisms underlying regulation
of cerebrovascular responses to anesthetic agents and the role
of this system in diseases in which either brain parenchyma or
endothelial function is compromised.
Jonas S. Johansson, M.D., Ph.D., University of Pennsylvania,
Philadelphia, Pennsylvania, FAER Young Investigator: "Interaction
of Volatile General Anesthetics and Proteins Assessed by Fluorescence
and Circular Dichroism Spectroscopy"
The proposal's central premise is that volatile anesthetics directly
alter protein function. Because a molecular description of this
interaction is vital to understanding mechanisms of action, the
binding of anesthetics to a model mammalian protein and the resulting
structural changes will be determined. The studies focus on the
neglected initial binding step between anesthetics and protein
and probe both local and global consequences. The target site
affinity for several general anesthetics will be determined using
tryptophan fluorescence quenching. This work also directly tests
the hypothesis that different anesthetics bind to the same protein
site. In addition, the effect of anesthetic binding on protein
structure and stability, and therefore protein activity, will
be characterized using fluorescence anisotropy and thermal denaturation
circular dichroism spectroscopy. Ultimately, optimization of anesthetic
structures should be feasible, based upon detailed descriptions
of the anesthetic-protein interaction, so that fewer side effects
and better therapeutic indices are achieved.
T. Philip Malan, Jr., M.D., Ph.D., University of Arizona, Tucson,
Arizona, FAER/Glaxo Wellcome Young Investigator: "Role of
C-fos Expression in the Regulation of Neuropathic Pain"
C-fos is a gene that regulates the function of a variety of other
genes in cells of the nervous system. The c-fos gene produces
Fos protein, which turns on target genes and causes them to make
their protein products. Pain produced by inflammation increases
production of Fos protein in the spinal cord. The Fos protein
thus produced interacts with target genes and causes the production
of substances that then decrease pain (pain produced by injury
to nerves, disease of nerves or abnormal functioning of nerves
increases the amount of Fos protein in spinal cord). By inhibiting
the synthesis of Fos protein using techniques of molecular biology,
we will also test whether production of Fos protein leads to events
that decrease intensity of neuropathic pain. It is hoped that,
understanding the mechanisms responsible for regulation of the
intensity of neuropathic pain will lead to novel therapies for
this difficult clinical problem.
Thomas N. Pajewski, M.D., Ph.D., University of Virginia, Charlottesville,
Virginia, FAER/ Zeneca Pharmaceuticals Young Investigator: "Anesthetic
Effects of Nitric Oxide Signaling in the Central Nervous System"
The mechanism of general anesthesia remains largely unknown; however,
the central component of many theories is the concept that it
is primarily the result of altered synaptic transmission. Previous
studies have suggested that perturbation of the nitric oxide signaling
pathway may represent a major cellular transduction system for
mediating the actions of inhalational anesthetics in the central
nervous system. The goal of this project is to improve our understanding
of the mechanisms of anesthesia by investigating the interaction
of the nitric oxide signaling pathway with key anesthesia-related
excitatory and inhibitory neurotransmitter pathways in specific
regions of the brain that are relevant to the anesthetic state.
Insight gained into general anesthetic mechanisms by these studies
may permit the design of new drugs or combinations of drugs that
may produce the anesthetic state but with fewer side effects.
Pamela A. Pierce, M.D., Ph.D., University of California, San
Francisco, California, FAER/Glaxo Wellcome Young Investigator:
"Role of Serotonin Receptor Subtypes in Peripheral Pain Mechanisms"
Serotonin (5-hydroxytryptamine; 5-HT) has long been known to produce
pain, hyperalgesia and inflammation and is believed to be involved
in a number of painful conditions, including both acute (e.g.,
operative wounds) and chronic (e.g., inflammatory arthropathies)
pain states important to the field of anesthesia and pain management.
Fifteen human and/or rat 5-HT receptor subtypes have been cloned
to date, yet little is known regarding the presence of these receptor
subtypes in peripheral sensory and sympathetic neurons involved
in pain neurotransmission. The specific aims of this research
are to use molecular techniques to identify the 5-HT receptor
subtypes in dorsal root ganglion (DRG) neurons and sympathetic
neurons, to determine which 5-HT receptors are expressed in DRG
nociceptors and to determine if expression of 5-HT receptor subtypes
in sensory and sympathetic neurons changes in the setting of pain
syndromes.
Adam Sapirstein, M.D., Massachusetts General Hospital/ Harvard
University, Boston, Massachusetts, FAER Young Investigator: "Mechanisms
of Cytosolic Phospholipase A2-Mediated Cell Death and Gene Regulation"
Increased phospholipase activity has been implicated in cellular
injury and death in conditions relevant to anesthesia and critical
care, including: ischemia and reperfusion, oxidant stress, inflammation
and sepsis. The goals of this project are to determine the mechanisms
by which the cytosolic phospholipase A2 potentiates cellular injury
and to evaluate how cells protect themselves from cytosolic phospholipase
A2-mediated injury. We hypothesize that phospholipase A2 can increase
oxidant-induced membrane and nuclear disruption and that phospholipase
metabolites can regulate the production of protective cellular
proteins. We have established a model of phospholipase A2 expression
in renal epithelial cells in culture. Experiments using recombinant
DNA techniques in this system will be conducted to test the hypotheses.
Knowledge of the mechanisms of phospholipase A2-mediated cell
injury and endogenous cell defenses will lead to important insights
into the general mechanisms of cell death and provide paradigms
for prevention and treatment of clinical conditions.
The FAER Board of Directors appreciates the continuing support
of Glaxo Wellcome Inc., Ohmeda Pharmaceutical Products, Society
of Cardiovascular Anesthesiologists and Zeneca Pharmaceuticals,
the Corporate Grand Sponsors who made possible the funding of
the above-named Young Investigator Awards.
Jonas S. Johansson, M.D., Ph.D., University of Pennsylvania, Philadelphia,
Pennsylvania, FAER Young Investigator: "Interaction of Volatile
General Anesthetics and Proteins Assessed by Fluorescence and
Circular Dichroism Spectroscopy". The proposal's central
premise is that volatile anesthetics directly alter protein function.
Because a molecular description of this interaction is vital to
understanding
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