MOLECULAR PATHOBIOLOGY OF PLATELET-ACTIVATING FACTORS

Project: Research project

Project Details

Description

Platelet-activating factor (PAF) is an important, perhaps pivotal, autacoid
with a myriad of phlogistic actions which implicates this mediator in
playing an important role in modulating many aspects of normal as well as
abnormal (patho)physiological and inflammatory processes. Most all of our
current understanding of the mechanisms underlying the (patho)biological
actions of PAF has been derived from studies that employed only the
hexadecyl-(C16:0) or octadecyl-(C18:0) alkyl chain PAF homologs. However,
it is now well-documented that the PAF synthesized by stimulated
neutrophils (PMN), as well as by other cells and tissues, is comprised of
a heterogeneous family of sn-2 acetylated phospholipids. Moreover, there
is now compelling evidence that various PAF homologs and analogs differ
significantly from one another in their instrinsic in vitro and in vivo
biological activities and potencies (e.g., platelet and PMN stimulation and
cardiovascular and pulmonary alterations), possibly by interacting with
different PAF receptor subtypes. Therefore, new research initiatives are
required to rigorously elucidate the extent of PAF molecular heterogeneity
and to characterize the (patho)physiological properties and mechanisms of
action of the various PAF molecules. In this regard, the overall objective
of the present study will be to address the following hypothesis:
Modulation of the types and amounts of the various molecular species of PAF
that are synthesized and released by the human PMN will significantly
influence the extent and character of PAF-mediated tissue injury and
dysfunction. Our investigations will focus on three Specific Aims: 1)
Characterization of the molecular composition of the PAF that is
synthesized and then either retained or released by human PMN after
stimulation by different stimuli; 2) Elucidation of the influence of the
intracellular and extracellular microenvironments on the molecular
composition of the PAF that is synthesized and then either retained or
released by stimulated human PMN; and 3) Characterization of the
mechanistic basis for the autocrine actions (agonistic, synergistic, and/or
antagonistic) of the PAF homologs and analogs that are synthesized by the
human PMN. The results of these studies will provide new information which
will be essential in our long-term efforts toward understanding the role of
PAF in the modulation of acute inflammatory and allergic tissue injury and
dysfunction.
StatusFinished
Effective start/end date4/1/782/29/00

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
  • National Institutes of Health
  • National Institutes of Health: $337,660.00
  • National Institutes of Health: $314,201.00

ASJC

  • Medicine(all)

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