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Joseph C.
Miller, PhD
Biochemical Mechanisms
of Cell Injury
My research focuses on
changes in cell membrane function during the
pathogenesis of cell injury. Alterations in
phospholipid metabolism, particularly the
involvement of calcium and phospholipases, are
being studied in models of myocardial cell
injury. Isolated cardiac myocytes
and membranes (subcellular
fractions) are utilized to investigate the
phenomena associated with the progression of
cell injury: accumulation of free fatty acids,
calcium loading, morphological damage, and ATP
depletion. We have demonstrated that hypoxia
produces increased fatty acid release and alters
alpha adrenergic receptor-stimulated
phosphatidylinositol turnover in isolated
myocytes. Similar changes have been observed
with the beta adrenergic receptor-adenylate
cyclase complex. We have demonstrated recently
that the protective role effects of dietary fish
oils containing omega-3 fatty acids may stem
from functional alterations of this adrenergic
receptor-effector system within the myocardial
cell membrane. Clearly, altered phospholipid
metabolism and membrane integrity correlate with
the onset of irreversible myocardial injury.
Abnormal phospholipase activity, and altered
intracellular calcium regulation, underlying
several of the hypotheses currently proposed to
explain the mechanism of cellular damage during
ischemia. A primary goal of my studies is to
delineate the biochemical etiology of cellular
injury involving several aspects of cell
function. By determining the pathogenic
mechanism(s) of myocardial cell injury, more
specific interventions may be designed to reduce
the damage resulting from ischemic or hypoxic
episodes.
An integrated battery of
analytical biochemical techniques is used to
characterize these changes in the various
models, including enzyme and receptor analysis,
metabolism of radioactive tracers, high-pressure
and thin-layer chromatography, and
microspectrofluorometry with the intracellular
dyes, such as fura-2, for calcium abnormalities.
The biological models range from isolated cell
cultures to whole animal studies. In addition,
we are utilizing experimental pharmacological
agents in attempts to prevent the transition of
injury from a reversible to an irreversible
stage.
Selected References:
JC Miller and PA Weinhold,
Cholinephosphotransferase in rat lung: The in
vitro synthesis of dipalmitoyl
phosphatidylcholine from dipalmitoyl glycerol. J
Biol Chem 256:12662-12665, 1981.
O Tone, JC Miller, IM Bell,
and SI Rapoport, Regional cerebral palmitate
incorporation following transient bilateral
carotid occlusion in awake gerbils. Stroke
18:1120-1127, 1987.
JC Miller, JM Gnaedinger,
and SI Rapoport, Utilization of plasma fatty
acid in rat brain: Distribution of
[14C]-palmitate between oxidative and synthetic
pathways. J Neurochem 49: 1507-1514, 1987.
RL Jones, JC Miller, HK
Hagler, KR Chien, JT Willerson, and LM Buja,
Association between inhibition of arachidonic
acid release and prevention of calcium loading
during ATP depletion in cultured rat cardiac
myocytes. Am J Pathology 135:541-556, 1989.
KH Muntz, M Zhao, and JC
Miller. Review: Down-regulation of myocardial
13-adrenergic receptors: Receptor subtype
selectivity. Circ Res 74:369-375, 1994.
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