| The research in my laboratory centers on the OGF-OGFr
axis. Initially, the laboratory, in collaboration
with Dr. Ian Zagon, utilized a multifaceted approach to
identify, isolate, and understand the individual
components of the OGF-OGFr axis - that is, the
pentapeptide OGF and its receptor, OGFr. Predicated
on observations of the presence of endogenous opioids that
regulated growth, the laboratory has identified [Met5]-enkephalin
(OGF) to be the most potent, and determined that it is an
autocrine and paracrine produced inhibitory peptide whose
action is receptor mediated. At the time of the
initial observations, the receptor was unknown. Our
laboratories have identified, isolated, biochemically and
pharmacologically characterized, morphologically revealed
the location and temporal expression, and molecularly
determined its cDNA and gene in mouse, rate, and
human. Because of the unique molecular structure and
dissimilarity with classical opioid receptors, the
receptor was termed opioid growth factor receptor,
OGFr. Its chromosomal location in humans has been
determined to be 20q13.3. My independent research focuses on two
topics: 1) the role of OGF-OGFr in normal cardiac
development, and cardiovascular development in light of
excess OGF or blockade of OGF-OGFr by the opioid
antagonist naltrexone (NTX) during prenatal and/or
postnatal development, and 2) the OGF-OGFr axis in
squamous cell carcinoma of the head and neck (SCCHN) with
an emphasis on the cellular and molecular factors
associated with tumor progression.
The project associated with heart development emanated
from my interests in developmental biology and
neurobiology. Our animal models for prenatal OGF or
NTX exposure resulted in both brain and heart
damage. While increased brain sizes, cell number,
and synapse profiles may be beneficial; increases in
cardiac growth can be associated with idiopathic dilated
cardiomyopathy. Further work on opioid receptor
blockade during development has revealed that NTX exposure
in utero may in fact be a novel model for dilated
cardiomyopathy. Rats subjected to continuous opioid
receptor blockade during prenatal life are born alive with
hearts that weigh more, have larger dimensions, and more
myocytes than controls throughout preweaning life.
As adults, these rats exhibit decreased heart rates,
decreased ventricular systolic function, and dilated
cardiomyopathy. (i.e., increased thickness of the left
ventricle free wall) - all hallmarks of dilated
cardiomyopathy. In conjunction with a pediatric
cardiologist, Dr. Kerry Rosen, our current studies focus
on the functional ramifications of this early insult on
cardiac development by echocardiography, and we have made
preliminary observations that heart rate and shortening
fraction are significantly compromised (i.e., decreased)
throughout adulthood in the rat. The clinical
corollary for this animal model includes pregnant women
who are treated with NTX for their alcoholism and drug
addictions. The project continues to evolve into
novel areas of wound healing/tissue repair following
myocardial infarction. This work may have clinical
implications in the therapy of heart attack.
A second project represents understanding the OGF-OGFr
axis in cancer development, progression, and
treatment. Because OGF is an inhibitory growth
factor, one might hypothesize that OGF plays a role in
inhibiting neoplastic growth and that cancerous states
represent a loss of OGF. We have just recently made
the intriguing discovery that it is not the loss of OGF,
but rather a defect in the receptor number, that is
characteristic of advanced stages of SCCHN. Building
upon the requisite in vitro and in vivo animal model
studies, the laboratory has recently been involved in
assaying tumor samples, as well as pathologically normal
specimens (i.e., tumor margins) from patients with SCCHN
for both gene and peptide expression. Using
quantitative Northern blot studies to examine for the OGFr
mRNA, as well as binding assays, western blot analysis,
and immunohistochemistry to assess protein levels, we have
documented that OGF receptors decrease significantly in
tumor tissue
|
