PATHOPHYSIOLOGY OF THE LACTOFERRINS

Project Details

Description

Lactoferrin (Lf), the principal and most avid Fe-binding protein in milk
and other epithelial secretions and the major constituent of the specific
granules of neutrophils, has been implicated in a wide variety of
functions. Its chief role appears to be defense against infectious
agents, through strong chelation of the Fe required for microbial growth,
but functions as diverse as Fe absorption in the gut, feedback
suppression of myelopoiesis and potent stimulation of macrophage and NK
toxicity, among many others, have been attributed to the molecule. Some
of these functions appear independent of Fe binding, and some relate to
the strong but unexplained binding affinity of Lf for nucleic acids.
Defects in Lf expression are observed in some cancers, and may contribute
to the pathogenesis or clinical manifestations of the disease. By virtue
of its profound affinity for Fe and multitude of related and unrelated
effects, Lf offers interesting potential as a therapeutic in infectious
diseases and neoplasms or as an immunomodulator. However, many of these
proposed functions of Lf are controversial and virtually all are unproven
at the physiological level. We have made the unique observation that
there are multiple forms of Lf. At least one isoform binds no Fe and
instead, expresses a potent ribonuclease activity. These isoforms have
similar, if not identical, primary structures and are not
interconvertible. It is our long-term objective to determine how the varied and powerful
functions of Lf can be exploited therapeutically. Our working hypothesis
is that the existence of multiple forms of Lf explains the broad and
often inconsistent functions proposed for Lf. In order to test this
hypothesis and ultimately to realize the therapeutic potential for the
isoforms, we must gain an understanding of Lf pathophysiology and
determine the precise in vivo role for each isoform. We also have the
opportunity to determine how isoforms with such similar structures could
express such disparate and nonoverlapping activities. This will be
accomplished by: 1. determining the structural differences that account
for the different activities of the isoforms; 2. determining the
significance of the avid DNA binding activity of Lf isoforms; 3. cloning
and expressing the isoforms; 4. examining structure-function
relationships in the isoforms using site-directed mutagenesis; 5.
analyzing the regulatory sequences that direct the unique tissue
distribution of Lf; 6. constructing transgenic lines of mice in which the
Lf gene has been disrupted and testing their phenotype and responsiveness
to infection and neoplasia.
StatusFinished
Effective start/end date5/1/933/31/01

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $214,305.00
  • National Institutes of Health
  • National Institutes of Health: $188,090.00
  • National Institutes of Health

ASJC

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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