Role of PAPP-A in Atherosclerosis

Project: Research project

Description

DESCRIPTION (provided by applicant): This proposal focuses on a newly recognized metalloproteinase in the insulin-like growth factor (IGF) regulatory system in atherosclerosis. IGFs play a critical role in the vascular injury response through their potent effects on cell proliferation, migration, survival and extracellular matrix production within the developing intimal lesion. IGF binding proteins (IGFBPs) produced by vascular cells modulate local IGF bioactivity through their control of IGF interaction with specific cell surface receptors. In vitro studies have implicated an inhibitory IGFBP, IGFBP-4, and a specific IGFBP-4 protease (IGFBP4-ase), so-called pregnancy-associated plasma protein A (PAPP-A), in cellular response to injury, including vascular injury. By cleaving IGFBP-4 in a highly regulated manner, IGFBP4-ase/PAPPA increases the pericellular IGF available for receptor activation. In vivo, IGFBP4-ase/PAPP-A expression is induced in injured coronary arteries paralleling the formation of neointima. Recently, IGFBP4-ase/PAPP-A immunoreactivity was demonstrated in culprit plaques of humans who had died of myocardial infarction, with the most intense staining in the inflammatory shoulder associated with smooth muscle cells, macrophages, and T-lymphocytes. Our overall hypothesis is that IGFBP4- ase/PAPP-A is a key IGF regulatory factor in the vascular response to injury leading to atherosclerosis and promoting plaque vulnerability. Utilizing cultured human cells and genetically engineered mice, the SPECIFIC AIMS of this proposal are to: 1) Determine the mechanisms underlying elevated IGFBP4-ase/PAPP-A in vulnerable plaque. 2) Determine the effect of IGFBP4-ase/PAPP-A deficiency on the development and progression of atherosclerotic plaque. 3) Determine the effect of targeted IGFBP4-ase/PAPP-A expression on the development and progression of atherosclerotic plaque. These studies seek to gain a better understanding of the cellular and molecular biology of atherosclerosis in order to establish a scientific basis for novel strategies to identify and limit plaque development, progression, and instability.
StatusFinished
Effective start/end date12/1/032/28/14

Funding

  • National Institutes of Health: $368,750.00
  • National Institutes of Health: $377,750.00
  • National Institutes of Health: $349,641.00
  • National Institutes of Health: $368,750.00
  • National Institutes of Health: $377,750.00
  • National Institutes of Health: $377,750.00
  • National Institutes of Health: $373,973.00
  • National Institutes of Health: $360,084.00

Fingerprint

Pregnancy-Associated Plasma Protein-A
Atherosclerosis
Somatomedins
Atherosclerotic Plaques
Insulin-Like Growth Factor Binding Protein 4
Insulin-Like Growth Factor Binding Proteins
Vascular System Injuries
Somatomedin Receptors
Protein Deficiency
Metalloproteases
Smooth Muscle Myocytes
Blood Vessels
Tunica Intima
Macrophages
Myocardial Infarction
Neointima
Staining and Labeling
Wounds and Injuries
Cell Surface Receptors

ASJC

  • Medicine(all)