MYLEOPEROXIDASE--ANALYSIS OF NORMAL &DEFICIENT STATES

Myeloperoxidase is an enzyme found in neutrophils that is thought
to play a significant role in host defense against microbial
infection. Myeloperoxidase deficiency affects one in two thousand
people making this the most common of the identified defects of
polymorphonuclear leukocytes. Neutrophils isolated from totally
deficient individuals have a severely diminished capacity to kill
micro-organisms. If also suffering from diabetes,
myeloperoxidase deficient people can have major systemic
infections. The enzyme is synthesized only during the
promyelocytic stage of myeloid differentiation and as a larger
precursor. It is extensively processed as it matures and is
transported to its correct subcellular compartment. With the goal
of understanding myeloperoxidase expression in both normal and
deficient people, we have isolated and sequenced cDNA and
genomic clones. We have found that normal humans produce two
messages for the enzyme and that the gene covers some 15
kilobases. To extend our knowledge of the myeloperoxidase gene
and its expression in normal and deficient states, the following
studies are proposed: 1. Characterize in detail the two mRNAs for myeloperoxidase and
identification of regions of the molecule important for transport
to its correct subcellular compartment. 2. Complete the characterization of the genomic clones and
identify sequences 5' of the coding region that regulate expression
of the gene. 3. Identify proteins that interact with the regulatory sequences
with the goal of understanding the tissue and temporal specificity
of myeloperoxidase gene expression. 4. Utilize the information about the mRNAs and gene expression
in normal people to begin the characterization of the lesions
involved in myeloperoxidase deficiency.