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Projects
We use the zebrafish as a model system to study
organ regeneration. Multiple zebrafish tissues are capable of
regenerating, both in the adult animal (e.g. fin, scales, heart,
liver, lateral line neurons and spinal cord) and in the embryo
(e.g. fin fold, lens, hair cells). The objective of this project
is to uncover the molecular pathways involved in organ
regeneration and in so doing, understand why some organs/tissues
appear to be endowed with regenerative potential while others do
not. A limited number of genes important in fin regeneration have
been identified previously through forward genetic screens in
zebrafish. We are currently embarking on a large-scale (3000-5000
genomes) forward genetic fin regeneration screen. Fin
regeneration mutants will also be challenged to regenerate other
structures including the heart, liver and fin fold. In this
fashion we hope to identify pathways common to regeneration in all
tissues, as well as tissue-specific mechanisms. In addition, we
have undertaken a pharmacological screen of 1280 compounds,
looking for inhibitors of fin regeneration. Preliminary results
(~200 compounds) have already identified 3 compounds that abrogate
fin regeneration. None of these compounds acts via a pathway that
has previously been shown to be involved in growth/regeneration.
We use zebrafish fin overgrowth mutants (both
spontaneous mutants and mutants identified through forward genetic
screens) to help dissect genetic pathways regulating growth and
size. Like humans, fish, and their fins, grow via a coordinated
process of allometric (juvenile) and isometric (adult) growth. As
one example, we are studying a mutant, rapunzel, which disrupts
isometric growth in the adult fin, resulting in profound fin
overgrowth. A positional cloning project of the rapunzel mutation
is nearing completion and identification of the genetic lesion
will provide further insight into the pathways coordinating
growth. Understanding the biology of growth control has important
implications pediatric medicine. A recent search of OMIM reveals
65 genetic syndromes associated with overgrowth. The molecular
pathogenesis of most of these syndromes is poorly understood and
therapies are limited.
For years it has seemed so simple…you eat, you
grow and you mature. Interestingly, the mechanisms coordinating
persons nutritional and growth status are not well understood.
For example, the Dutch famine of 1945 taught us that fetal growth
proceeds largely unabated in the face of severe maternal
nutritional deprivation and wasting. Using zebrafish fin growth
as a model system, we have demonstrated that in fish, like humans,
the relationship between nutritional status and growth is complex.
For example, although fasting rapidly abrogates fin growth in
adult zebrafish, growth of the fin in fasted juvenile zebrafish,
persists. We are using genetic, pharmacologic and physiologic
tools to dissect the pathways integrating nutrition and growth.
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SCHOOL OF MEDICINE
