Project: Research project

Project Details


The long-term goal of the applicant is to explore a paradigm of
disease, hypothesizing that in the nephrotic syndrome, both
proteinuria and hypercholesterolemia have a causative role in the
development of interstitial inflammation and fibrosis. The
applicant proposes that these two components of the nephrotic
syndrome contribute separately but synergistically to this
process, which inevitably leads to end-stage renal disease when
proteinuria is unremitting. In this project, the applicant will
focus on the role of the interstitial macrophage, and on the
macrophage product, TGF-beta, in the generation of interstitial
fibrosis. The TGF-beta family is a group of multifunctional
peptides which influence growth, differentiation and
morphogenesis. It is proposed that TGF-beta plays a pivotal
profibrotic role in the interstitium in proteinuric renal
disease. The effects of hypercholesterolemia on macrophage
infiltration and activation will be addressed. Two animal models
of proteinuria (one normocholesterolemic and one
hypercholesterolemic) will be used; complementary experiments in
cell culture systems will also be performed. In vivo
interventional studies in animal models will be utilized to
identify the infiltrating macrophage as the origin of TGF-beta
upregulation, as well as to explore the role of
hypercholesterolemia in macrophage activation. Proof of TGF-beta
activation in the interstitium will be obtained via bioassay for
the peptide, and will also be demonstrated indirectly by
identifying "downstream" effect of TGF-beta upregulation in the
interstitium. These processes will be documented with molecular
biological and immunohistochemical methods in whole animal and
cell culture models. Particular focus will be placed on the role
of proteases in this system, both on the exploration of
proteolytic steps necessary for TGF-beta activation, and on the
effect of TGF-beta upregulation on matrix metalloproteinase
production in the interstitium.
Effective start/end date9/1/958/31/00