DESCRIPTION (provided by Candidate): Children with the rare congenital disorders of glycosylation (CDG) have a mutation in one of the many genes required for N-linked protein glycosylation and of 38 distinct subtypes, 37 have no treatment options. Mutation of mannose-6-phosphate isomerase (MPI) causes the gastrointestinal type of CDG. It is not understood how defective synthesis of the lipid-linked oligosaccharide (LLO) in CDG patients results in multi-systemic abnormalities and few CDG animal models exist. zebrafish provide a powerful vertebrate system to study monogenic disorders with their high genetic conservation to humans, and morpholinos offer rapid and efficient gene knockdown. I used morpholino technology to establish mpi morphants with less than 15% residual Mpi enzyme activity. They develop defects in the head, eye, gut, liver, and body shape with increased cell death in affected tissues. MPI-CDG is the only CDG with a known treatment: oral mannose increases flux through hexokinase and a minor complementary metabolic pathway that produces mannose-6-phosphate and normalizes protein glycosylation, relieving most symptoms. Similarly, both the morphologic and cell death phenotype in mpi morphants are almost completely rescued by mannose supplementation. My preliminary data in a novel zebrafish model of MPI-CDG implicate activation of the tumor suppressor, p53, in CDG pathology. Our objective is to determine whether the well known tumor suppressor, p53, has a novel role in the mechanism of disease in MPI-CDG. Our central hypothesis is that p53 is responsible for disease in MPI-CDG and will determine the mechanism by which p53 affects either metabolic alterations in glycosylation or apoptosis. Specific Aims: 1: Establish the relationship between p53 activation, mannose metabolism, and Mpi deficiency. 2: Determine whether MPI-CDG is a result of abnormal LLO or glycoprotein formation. 3: Determine the contribution of p53-mediated apoptosis to the mpi morphant phenotype. My long-term goal is to understand the molecular basis of CDG with a focus on the associated gastrointestinal disorders. The underlying genetic defect in CDG is simple and well understood. I will then apply this knowledge to more common causes of these same diseases in pediatric patients, as non-alcoholic fatty liver disease, fibrosis, and cirrhosis are all associated with defects in protein glycosylation.
|Effective start/end date||13/09/13 → 31/07/16|
- National Institute of Diabetes and Digestive and Kidney Diseases: $869.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $151,416.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $151,376.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $150,876.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $99,036.00
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