CELLULAR MECHANISMS IN ATHEROGENESIS

  • Sprague, Eugene A (PI)
  • Kelley, Jim (PI)
  • Lewis, Douglas (PI)
  • Ghidoni, John (PI)
  • Nerem, Robert (PI)
  • Schwartz, Colin (PI)

Project: Research project

Project Details

Description

This multidisciplinary renewal probes mechanism in atherogenesis,
emphasizing those cells implicated in pathogenesis, namely EC, SMC,
and the mononuclear phagocyte (MP). After major revisions,
including the deletion of one project, and the complete
restructuring of another, the more focused PROGRAM PROJECT
comprises 4 complementary projects and 4 core units. PROJECT A
employs a parallel plate channel flow viscometric device to explore
biologic responses of vascular EC to steady state and oscillatory
laminar shear stress, emphasizing changes in cell stiffness,
intracellular potential and LDL and Ac-LDL receptor expression and
function. Mechanisms of hemodynamic signal transduction are
examined with emphasis on EC membrane fluidity (DPH),
phosphoinositide turnover, Ca++ mobilization (Fura 2), and
cytoskeletal function. In PROJECT B, a major thrust is the
expression of the MP Acetyl-LDL receptor with emphasis on the
regulatory role of MP activation and differentiation. This project
will isolate, purify, and characterize the Ac-LDL receptor of
rabbit granuloma macrophages, including its complete primary amino
acid sequence. Studies will examine the relative contributions of
receptor and non-receptor mediated pathways (pino-phagocytosis) for
Lp uptake and metabolism (LDL, Ac-LDL, beta-VLDL) by granuloma
macrophages from normal and WHHL rabbits, and the influence of
induced activation (gamma-IFN, LPS) on MP Lp receptor expression
and function. PROJECT C, focuses on the biology of MP recruitment
to the arterial intima. A major emphasis is to determine the
structural and functional homology of the 12Kd monocyte
chemoattractant (SMC-CF) secreted by arterial SMC and the
chemoattractant isolated from lesion-prone areas of the pig aorta
(SACF). Studies will compare these two chemoattractants
immunochemically, and in terms of receptor expression, and will
characterize the biologic functions of SMC-CF both in vitro and in
vivo. In vivo studies utilize two established models, namely the
Alzet osmotic pump to deliver SMC-CF to the pig aorta, and the
Florey rabbit ear chamber. PROJECT D employs glycoprotein
processing inhibitors to probe the roles of N linked
oligosaccharides in cultured SMC and normal, internalization-
defective and receptor-negative FH fibroblasts on LDL receptor
synthesis, processing, recycling and LDL metabolism in terms of
lysosomal targeting and activities. All 4 projects depend upon
CORE units in cell culture, biochemistry, pathology and
administration. Quality is monitored by internal and external
advisory committees.
StatusFinished
Effective start/end date7/1/826/30/94

Funding

  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)

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