NEUROFIBROMATOSIS--A MODEL SYSTEM USING PHORBOL ESTERS

  • Ciment, Gary, (PI)

Project: Research project

Project Details

Description

The syndrome associated with the human genetic disease von Recklinghausen
neurofibromatosis (NF) has a number of features which suggest that some of
the neural crest-derived cells in these patients have become unstable in
their phenotype. Some of the glial cells of peripheral nerves divide
uncontrollably and undergo a metaplastic transformation into melanocytes.
In previous work, we found that the phorbol ester TPA induces similar
changes in crest-derived cells of early avian embryos. Some of the glial
cells of the dorsal root ganglia (DRG) of quail embryos, exhibit abnormal
growth characteristics and transform into melanocytes when cultured in the
presence of TPA. We wish to determine the extent to which TPA treatment of embryonic avian
cells mimics other features of the NF syndrome in patients. Since
NF-associated tumors are almost exclusively associated with neural crest
and neuroectodermal derivatives, we will first test whether the TPA-induced
metaplasia of embryonic avian cells shows a similar embryological
specificity. This will involve treating various quail tissues with TPA in
culture, grafting them into host chicken embryos, and then comparing the
range of derivatives to which they give rise. A second feature of human NF
is the progression of some NF-associated benign tumors to a malignant
state. We will determine whether treatment with TPA (possibly in
conjunction with a carcinogen) in culture will cause these embryonic avian
cells to develop into either benign or malignant NF-like tumors when
grafted into host embryos. Since a third feature of human NF is the
changes in severity of symptoms at puberty or with pregnancy, we will test
whether various hormones and/or peptide growth factors can influence the
TPA-induced metaplastic transformation of avian DRG cells. In addition, we will test whether TPA induces a similar transformation in
mammalian DRG cells, and will perform experiments to determine whether TPA
exerts these effects on avian embryonic cells via stimulation of protein
kinase C, as has been shown in a number of other systems. This proposal is designed to examine the possibility that phrobol esters
might bring about cellular changes in avian embryonic cells which mimic the
pathophysiological changes resulting from the NF mutation, and therefore
would serve as a model system for this disease.
StatusFinished
Effective start/end date7/1/866/30/97

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $119,458.00
  • National Institutes of Health
  • National Institutes of Health: $213,753.00

ASJC

  • Medicine(all)
  • Neuroscience(all)

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