• Gendler, Sandra J (PI)
  • Xiu, Chang (PI)
  • Ghanbari, Ray (PI)
  • Hanrahan, John (PI)
  • Clapham, David (PI)
  • Riordan, John (PI)

Project: Research project

Project Details


Advances in understanding of the molecular basis of cystic fibrosis,
although still far from complete, have enabled the initiation of new
approaches to therapy. Several strategies are feasible, but it is not
yet possible to predict which will be successful. Gene therapy is the
most direct and obvious approach and is appropriately being intensively
pursued. Additionally, new knowledge of the steps between mutations in
the CFTR gene and pathological changes in the patient provide other
potential sites of intervention. This SCOR will focus on four of these.
Project I will further elucidate the molecular events involved in the
biosynthetic arrest and subcellular mislocalization of deltaF508 CFTR
which is present in more than 90% of patients. Very recent evidence
suggests that the formation of a complex between the mutant molecule and
a chaperone which is resident in the endoplasmic reticulum may contribute
to the intracellular retention. Perturbation of the tight complex which
the mutant molecule forms with the chaperone may be possible with
inhibitors of glycosylation because oligosaccarides are required for
complex formation. Project II aims to enhance the functional capacity
of CFTR by genetically changing it or by altering the phosphorylation-
dephosphorylation cycle involved in its regulation, a maneuver which can
activate several mutant forms of CFTR when certain phosphatase inhibitors
are employed. Project III will pursue exciting new findings on a
molecular network which mediates osmotic regulation of cellular chloride
permeability. One member of this group, IClnm, has been cloned and
characterized and now provides a means of access to other molecules
involved, including a novel chloride channel with properties distinct
from those previously described. It may be possible to circumvent the
defective CFTR chloride channel by harnessing this pathway. Project IV
approaches the CF problem still further downstream from the CFTR at the
level of mucin production. Using recently-generated DNA and antibody
probes for different members of the mucin super family, the basis of
mucin overexpression in CF will be explored at the level of the mucus
cells themselves. The ultimate objective is to learn enough about the
mechanism of up-regulation to be able to prevent or reduce it. These
four projects will rely on four scientific core resources, including
cellular and transgenic expression, sophisticated multi-label subcellular
imaging and access to large CF clinic facilities.
Effective start/end date9/30/948/31/97


  • National Institutes of Health
  • National Institutes of Health


  • Medicine(all)


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