| Hudson Freeze, Ph.D. |
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2009 Conference abstract
Deficient Heparan Sulfate and N-Glycosylation Contribute to Protein-Losing Enteropathy in Humans and Mice
Hudson Freeze, Ph.D.
Genetic Disease Program, Sanford Children’s Health Research Center, Burnham Institute for Medical Research, 10901 N. Torrey
Pines Road, La Jolla, CA 92037.
e-mail: hudson@burnham.org.
Protein losing enteropathy (PLE), the loss of plasma proteins through the intestine, occurs in Congenital Disorders of
Glycosylation (CDG) and long after corrective heart surgery (Fontan procedure) in some children. We believe that environmental
insults (inflammatory challenge and increased venous pressure) precipitate PLE in genetically at-risk patients. Curiously, these
PLE patients lose heparan sulfate (HS) from the intestinal epithelial cells, but it returns when PLE subsides. We wanted to model
PLE in epithelial cells, intestinal explants, and mice to understand how N-glycosylation and HS loss contribute to PLE. Results
from cell monolayers, mucosal explants, and from mice were fully consistent. Mice lacking HS on their intestinal epithelial cells
increase enteric protein loss, which is greatly compounded when venous pressure and/or TNFa/IFNg challenge are also imposed.
HS normally blunts cytokine effects by preventing cytokine binding and/or signaling that destabilizes tight junctions allowing
protein leakage. Non-anticoagulant heparin reverses protein loss in HS-deficient cells and mice. Heparin injections also reverse
PLE in post-Fontan and CDG patients. To determine effects of reduced N-glycosylation, we knocked down phosphomannose
isomerase (PMI/Mpi, Fru-6-P <--> Man-6-P) in epithelial cells. Protein leakage increased and cytokine challenge further
exacerbated it. However, HS loss and PMI deficiency were additive, suggesting that impaired N-glycosylation does not cause HS
loss. We have now made a PMI hypomorphic mouse containing a patient mutation. This line also shows increased enteric protein
leakage in feces and in through mucosal explants. A combination of HS loss and N-glycosylation deficiency increases intestinal
permeability leading to enteric protein leakage. Non-anticoagulant heparin may be therapeutic for PLE. Clinical trials are in early
stages.
Supported by NHLBI, the Children’s Hearts Fund, and the March of Dimes Foundation.
Deficient Heparan Sulfate and N-Glycosylation Contribute to Protein-Losing Enteropathy in Humans and Mice
Hudson Freeze, Ph.D.
Genetic Disease Program, Sanford Children’s Health Research Center, Burnham Institute for Medical Research, 10901 N. Torrey
Pines Road, La Jolla, CA 92037.
e-mail: hudson@burnham.org.
Protein losing enteropathy (PLE), the loss of plasma proteins through the intestine, occurs in Congenital Disorders of
Glycosylation (CDG) and long after corrective heart surgery (Fontan procedure) in some children. We believe that environmental
insults (inflammatory challenge and increased venous pressure) precipitate PLE in genetically at-risk patients. Curiously, these
PLE patients lose heparan sulfate (HS) from the intestinal epithelial cells, but it returns when PLE subsides. We wanted to model
PLE in epithelial cells, intestinal explants, and mice to understand how N-glycosylation and HS loss contribute to PLE. Results
from cell monolayers, mucosal explants, and from mice were fully consistent. Mice lacking HS on their intestinal epithelial cells
increase enteric protein loss, which is greatly compounded when venous pressure and/or TNFa/IFNg challenge are also imposed.
HS normally blunts cytokine effects by preventing cytokine binding and/or signaling that destabilizes tight junctions allowing
protein leakage. Non-anticoagulant heparin reverses protein loss in HS-deficient cells and mice. Heparin injections also reverse
PLE in post-Fontan and CDG patients. To determine effects of reduced N-glycosylation, we knocked down phosphomannose
isomerase (PMI/Mpi, Fru-6-P <--> Man-6-P) in epithelial cells. Protein leakage increased and cytokine challenge further
exacerbated it. However, HS loss and PMI deficiency were additive, suggesting that impaired N-glycosylation does not cause HS
loss. We have now made a PMI hypomorphic mouse containing a patient mutation. This line also shows increased enteric protein
leakage in feces and in through mucosal explants. A combination of HS loss and N-glycosylation deficiency increases intestinal
permeability leading to enteric protein leakage. Non-anticoagulant heparin may be therapeutic for PLE. Clinical trials are in early
stages.
Supported by NHLBI, the Children’s Hearts Fund, and the March of Dimes Foundation.
Research authored by Dr. Freeze
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List of Publications via PubMed
(NIH National Library of Medicine)
List of Publications via PubMed
(NIH National Library of Medicine)
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