Project Details

Description

Lysosome function is essential for the normal development and good health
of humans and other higher organisms. Patients with deficiencies in
individual or multiple lysosomal enzymes exhibit acute and chronic health
problems including mental retardation, developmental deformities, cardiac
impairment, and premature death. Most lysosomal enzymes are delivered
to the lysosome by the mannose 6-phosphate dependent targeting system.
In this pathway, lysosomal enzymes are phosphorylated on selected mannose
residues by a lysosomal enzyme phosphotransferase. The
phosphotransferase is defective in patients with mucolipidosis II and
III, which results in improper targeting of lysosomal enzymes. In normal
individuals, the phosphorylated lysosomal enzymes bind to small and large
mannose 6-phosphate receptors which then deliver the enzymes to
lysosomes. the objectives of this research project are to understand the
mechanism of lysosomal enzyme targeting and the molecular basis for
mucolipidosis II and III. there are three specific aims. 1) cDNAs
encoding the lysosomal enzyme phosphotransferase will be isolated by
expression cloning, sequenced to determine the phosphotransferase's
primary structure, and used to identify the molecular lesion in patients
with mucolipidosis II and III. 2) Mammalian cell lines lacking either
or both types of mannose 6-phosphate receptors will be created using
targeted gene disruption and transfection experiments. The cells will
be analyzed to determine the relative functions of the small and large
mannose 6-phosphate receptors in lysosomal enzyme targeting. 3) The
molecular basis for large mannose 6-phosphate receptor function will be
investigated by transfecting cultured cells with mutant receptors and
analyzing their ability to target lysosomal enzymes. In addition, the
unique reagents created in this research will facilitate development of
targeted enzyme replacement therapies to treat patients with many
different lysosomal storage disorders.
StatusFinished
Effective start/end date3/1/932/28/02

Funding

  • National Institutes of Health
  • National Institutes of Health: $250,392.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $10,000.00
  • National Institutes of Health
  • National Institutes of Health: $172,475.00
  • National Institutes of Health: $273,612.00
  • National Institutes of Health

ASJC

  • Medicine(all)

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