Project: Research project

Project Details


DESCRIPTION (Adapted from Applicants Abstract): Mammalian heart
development involves an extraordinarily intricate set of processes that
include cellular proliferation, migration, and differentiation. Growth
factors have been localized to myocardial cells during many of these
events. However, the precise function and mechanism of these factors
during early embryonic cardiac development, as well as the ramifications
of disturbances in the expression of these growth factors, are not
known. This laboratory has examined the role of endogenous opioid
systems in cardiac development, and found that acute opioid antagonist
blockade by naltrexone (NTX) resulted in increases in DNA synthesis in
epicardial and myocardial cells of the ventricles and atria in neonatal
rat heart. Chronic exposure to NTX for 10 days resulted in increases
in weight and size of the heart, as well as enhanced DNA synthesis.
Moreover, they have identified [Met5]-enkephalin (termed the opioid
growth factor (OGF)), as a potent inhibitor of DNA synthesis in both
embryonic and neonatal heart. Preliminary evidence suggests the presence
of both OGF and its receptor (zeta) in heart tissue. The hypothesis of
this application is that endogenous opioid systems regulate cardiac
development. These studies will examine the role of endogenous opioid
systems in embryonic and postnatal heart development using NTX to
disrupt the tonic interaction of opioids and opioid receptors. Specific
aims include: 1) define the role of the endogenous opioid system on
cardiac growth using [3H]-thymidine incorporation and autoradiography;
and 2) explore the ramifications of chronic exposure to NTX during
prenatal and postnatal life on cardiac morphology. This application
also will focus on one opioid growth factor known to regulate
cardiogenesis (OGF). Additional specific aims in this area include: 3)
determine the temporal and spatial distribution of OGF by
immunocytochemistry and radioimmunoassay, and prohormone gene expression
by Northern blot analysis and in situ hybridization. 4) assess the
biochemical characteristics of the zeta opioid receptor in the
developing rat heart using receptor binding assays, and the presence and
distribution of binding sites by in vitro autoradiography; and 5)
ascertain the direct influence of OGF and NTX on growth of neonatal
ventricular myocardium using tissue culture. These data will contribute
to our knowledge of basic cardiac biology, and will examine the
influence of endogenous opioid systems in regard to heart development
and dysmorphogenesis.
Effective start/end date1/1/9412/31/00


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