• Abboud, Hanna E (PI)

Project: Research project

Project Details


The long term goal of this proposal is to determine the role of growth
factors in the proliferative and sclerotic process that accompanies
progressive glomerular diseases. The central hypothesis is that
platelet-derived growth factor released by activated mesangial cells or
infiltrating inflammatory cells and platelets actively participate in
glomerular hypercellularity. Moreover, we hypothesize that an interplay
between the expression-of PDGF and transforming growth factor-beta
(TGF-beta) determine the progression of proliferative and sclerotic
processes. To correlate growth factor expression with morphologic and
functional changes, we will quantify PDGF and TGF-beta mRNAs expression
and their translated proteins as well as their receptors in mouse kidneys
of experimental glomerulonephritis models using solution hybridization
assays, in situ hybridization and immunohistochemical techniques. We
will utilize two mouse models of IgA nephropathy and lupus nephritis. To
determine the time course of onset and progression of renal fibrosis, we
will determine the rates of collagen synthesis in vivo in experimental
and control animals and determine if the changes in collagen synthetic
rates are associated with a preferential increase in any of the collagen
subtypes. Levels of mRNAs encoding for specific collagen chains, will be
quantified by Northern blotting or solution hybridization, and in situ
hybridization; transcription rates will be assessed by nuclear run on
assays. We well determine the contribution of decreased collagen
degradation to fibrosis by measuring the activity and distribution of
collagenase(s) and inhibitor. To establish a role for growth factors in
mediating the renal injury, we will assess the effect of therapeutic
intervention on growth factor expression and progression of renal
disease. In the in vitro studies, we will determine the contribution of
transcriptional and posttranscriptional mechanisms to the changes in PDGF
mRNAs levels in response to growth factors and cAMP. We will determine
if the opposing actions of cAMP and phorbol esters on A chain gene
transcription are mediated by the same DNA response element and
characterize the protein DNA interaction by gel retardation and DNAase
foot printing assays. To determine if intracellular or secreted PDGF
acts in an autocrine manner to regulate DNA synthesis, we will first
identify the PDGF isoform secreted by mesangial cells and the PDGF
receptor subtype the cells express and then utilize specific anti-PDGF
antibodies added exogenously or microinjected into mesangial cells to
shut off DNA synthesis. In addition, we will study the effect of
selective PDGF gene inhibition utilizing antisense RNA transfection
strategy on DNA synthesis. These studies should help establish a role
for PDGF and TGF-beta in glomerular injury and determine the molecular
mechanisms involved in PDGF A chain regulation.
Effective start/end date5/15/913/31/02


  • National Institutes of Health: $176,842.00
  • National Institutes of Health: $164,820.00
  • National Institutes of Health: $198,875.00
  • National Institutes of Health: $187,427.00
  • National Institutes of Health: $158,919.00


  • Medicine(all)


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