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Thomas F. Tracy, Jr., M.D.
With the successful
transfer of Dr. Tracy's NIH Grant, the institution has extended
a generous level of new direct support and renovation of an additional
1000 sq. ft of laboratory space. A Senior Research Assistant
and an instructor-level Post Doctoral Fellow are funded. It is
clear that the residents will be exposed to this basic science
research activity in the molecular and cellular aspects of liver
injury and repair. The resident will be introduced to lab meetings
and the grant activity that is part of the Division. Collaborative
discussions have been started with an eye to the development
of Program Project Grants that can bridge Surgery and Pediatrics
in the areas of hepatic gene transcription and liver stem cells.
Current funding focuses on matrix metabolism during liver repair.
The cellular control of matrix metalloproteinases (MMP) is studied
using novel assays to localize and quantify MMP activity.
References:
Roggin K K, 2000, Lechner AJ, 1998, Olynyk JK, 1998, Fox ES, 1997, Fox ES, 1996(a), Tracy TF, 1996(a), Neuschwander-Tetri BA, 1996, Fox ES 1996(b), Tracy TF, 1996(b)
Arlet
G. Kurkchubasche, M.D.
Interests focus on the management
of disorders of GI function, particularly as related to the Short
Bowel Syndrome, and originated during the research years at the
University of Pittsburgh, Children's Hospital. The basic science
research on transmucosal bacterial passage in an in vitro (Ussing)
model provided some of the fundamental principles involved in
protecting a compromised intestinal barrier, both in premature
neonates at risk for NEC and the older infant with intestinal
dysfunction. The clinical responsibilites in caring for infants
and children with short bowel syndrome spurred ongoing interest
in this field. This was expanded, through mentoring from Dr.
Tracy at St. Louis University and subsequently here at Brown
Medical School, to the impact of sepsis and intestinal dysfunction
on hepatic function. For a brief period of time this involved
direct participation in the NIH-funded laboratory activities
in Dr. Tracy's lab, leading to some joint publications on quantification
of hepatic fibrosis. An endotoxin vaccine was investigated in
terms of its effect on hepatic fibrosis after bile duct ligation.
The nutritional management of the surgical infant remains focused
on the prevention and/or reversal of cholestatic jaundice. As
part of this ongoing interest, Dr. Kurkchubasche has currently
become involved in the research committee of the American Society
for Parenteral and Enteral Nutrition (ASPEN). She continues to
be involved in advances in the care of infants with SBS and has
offered the serial transverse enteroplasty procedure with successful
enteral adaptation.
Roggin K K, 2000, Ambruso
DR 2000, Roggin
KK 2001, Kurkchubasche AG 1998
Christopher
S. Muratore, M.D.
Our laboratory is interested
in understanding the processes that govern normal and accelerated
lung development. The purpose of our research is to address the
question: the effect of stretch on the expression of vascular
endothelial growth factor and its receptors (Flt-1, KDR) utilizing
primary alveolar type II cell cultures and in vivo tracheal occlusion
studies. Moreover, the mechanism of stretch-related growth following
fetal tracheal occlusion will focus on cytoskeleton-mediated
signaling through RhoA/Rho kinase interaction with VEGF.
The importance of mechanical forces in fetal lung development
has been well established. From episodic fetal breathing movements
to the secretion of lung liquid, the role of mechanical stretch
is an important contributor to normal alveolar differentiation.
The signal transduction pathways regulating these processes remain
largely unknown. However, there is evidence to suggest interaction
from the cytoskeleton via RhoA/Rho kinase signaling as potential
mediators during development.
Furthermore, there is considerable evidence in other organ systems
to suggest that the rate of organ growth may ultimately be governed
by the vascular endothelium. Previous findings that alveolar
growth following fetal tracheal occlusion was closely tied to
capillary growth would suggest that the lung behaves this way
also. The derived hypothesis was that stimulation of pulmonary
alveolarization following stretch from fetal tracheal occlusion
was secondary to upregulation of the potent endothelial cell
mitogens such as vascular endothelial growth factor (VEGF) and
that the endothelial cell represents the central stimulus of
parenchymal lung growth. If this hypothesis is correct, we would
expect: 1) upregulation of vascular endothelial cell mitogens
such as vascular endothelial growth factor (VEGF) to occur in
response to stretch and tracheal occlusion 2) that lung growth
will be enhanced by administration of endothelial cell mitogens
such as VEGF to either whole animal, lung explants, or cultured
cells 3) that addition of inhibitors of endothelial proliferation
to otherwise normal fetal lungs will result in pulmonary hypoplasia.
Despite advances in neonatal critical care, infants born with
congenital diaphragmatic hernia (CDH) and profound pulmonary
hypoplasia remain unsalvageable. Lessons learned from investigations
of the effects of fetal tracheal ligation on lung growth carried
out in many laboratories has focused interest on developing therapies
to actively promote fetal and neonatal lung growth. As a consequence,
an NIH-funded, randomized trial of fetal endoscopic tracheal
occlusion was investigated in an attempt to improve pulmonary
hypoplasia in human fetuses with CDH. The results were mixed
however. Tracheal occlusion did not improve survival or morbidity
rates. The results demonstrated that patients that had fetal
tracheal occlusion at 23 to 27 weeks of gestation had results
that were similar to "conventional" postnatal management.
This result was disappointing since there is an abundance of
experimental evidence that supports the notion that occlusion
of the fetal trachea will stimulate lung growth. Although cell
stretch created by retained fetal lung liquid is presumed to
be the stimulus for growth following fetal tracheal occlusion,
the underlying molecular mechanisms responsible for the alveolar
multiplication seen is not at all understood.
Francois
I. Luks, M.D.
Previous research has focused
on endoscopic fetal surgery and access to the fetal trachea,
in a large animal model (sheep). Projects have mainly centered
around fetal lung development and mechanisms of accelerated lung
growth after fetal tracheal occlusion. This was done in conjunction
with the Pathology Department (Monique E. De Paepe, M.D.) and
has been funded by the American Lung Association. In addition
to the ovine model, a small animal model (fetal rabbit) and in
vitro studies have been conducted into the fate of type II pneumocytes
and the role of apoptosis in normal and accelerated fetal lung
development.
One or more undergraduate and medical students from Brown
University are given the opportunity each year to participate
in the various fetal research projects.
More recently, fetal research
has focused on the pathophysiology of twin-to-twin transfusion
syndrome (TTTS). Following the development of a clinical program
in fetal surgery and our participation (as the only North-American
center) in the randomized trial on treatment for TTTS, we are
now pursuing more basic research in the mechanisms of TTTS, and
are developing an animal model for the condition. Clinical research
in this field includes the search for markers of outcome in TTTS.
New collaborations with the Division of Engineering
have yielded research projects in non-invasive monitoring during
fetal surgery and the development of advanced image display systems
for laparoscopic surgery, in a partnership with Brown and the
industry. The research is conducted with graduate students in
Engineering and Economics, medical students and surgical residents,
and grant support is being sought from the Science and Technology
Advisory Committee of Rhode Island and the Food and Drug Administration.
References:
De Paepe ME 1999, Papadakis K, 1998(a), Papadakis K 1998(b), De Paepe ME 1998, Luks FI 1997, Papadakis K 1997, Luks FI 1996(a), Luks FI 1996(b)
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