BASIS OF OXYGEN-DEPENDENT NEUTROPHIL HOST DEFENSES

Project: Research project

Description

The goal of this Program Project Grant is to advance cellular,
biochemical and molecular understanding of phagocyte biology,
microbicidal systems and clinically relevant disorders of antimicrobial
function. The target cell is the human neutrophil and the major theme
is the fundamental basis for oxygen-dependent systems in the
inflammatory response and host defenses. Three projects, each directed by an established investigator, constitute
an integrated approach to the scientific goals. Project 1 will
determine the structure and function of cytosolic proteins that play
essential roles in activation of the superoxide-generating NADPH oxidase
system. The studies include characterization of the inherited deficiency
state of two cytosolic proteins in two different autosomal forms of
chronic granulomatous disease. In Project 2 electron spin resonance
spectroscopy will be the key analytical tool for defining physical
chemical and cellular factors that modulate the formation of hydroxyl
radical by activated neutrophils. Project 3 deals with molecular
aspects of the expression and intracellular processing of
myeloperoxidase, an important enzymatic constituent of oxygen-dependent
microbicidal function. The Xenopus oocyte expression system and
sequence analysis of abnormal restriction enzyme fragments from patients
with hereditary myeloperoxidase deficiency will be used to characterize
normal and aberrant proenzyme processing. The interplay among the individual projects is extensive at both
conceptual and technical levels. Specific receptor-ligand-cytoskeletal
interactions lead to oxidase activation events (Project 1 which in turn
result in the formation of activated species of oxygen that require in
part the secretion of myeloperoxidase for the expression of microbicidal
activity. The investigators' laboratories are in favorable proximity to
facilitate programmatic approaches and core resource development. Two
proposed scientific cores will provide cell preparation and culture
support and analytical facilities whereas overall program management
will be coordinated through the administrative core. Institutional
environment and support are also very favorable including such core
facilities as protein structure, molecular biology, ESR spectroscopy,
hybridoma, electron microscopy, image analysis, and fluorescence-
activated cell sorting. Thus, the Program Project Grant will take
maximum advantage of the complementary scientific expertise of the
investigators, the proposed core facilities and existing institutional
features to attack important problems in neutrophil biology.
StatusFinished
Effective start/end date8/1/897/31/95

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

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Neutrophils
Peroxidase
Oxygen
Iron
Cell Culture Techniques
Spin Trapping
Phagocytes
Lactoferrin
Research Personnel
Free Radicals
Copper
Restriction Mapping
Enzyme Precursors
Proteins
Systems Biology
Eosinophil Peroxidase
Hybridomas
Iron Chelating Agents
Xenopus
NADP

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)