IPA for Luisa Isabel Morales Nebreda

Project: Research project

Project Details


A number of pharmacologic or genetic interventions have been shown to prevent the
development of fibrosis following the intratracheal administration of bleomycin, a
commonly used model for the study of lung fibrosis. These studies have provided
important mechanistic insights into the development of pulmonary fibrosis and have
identified both transforming growth factor-beta (TGF-beta) and peroxsome prolifeatoractivated
receptor-gamma (PPAR-gamma) as important mediators of fibrosis. In our preliminary
data, we observed that the administration of a proteasome inhibitor to mice 8 days after
the administration of bleomycin resulted in marked attenuation of lung fibrosis. Similar
protection was observed in a bleomycin induced skin fibrosis model of scleroderma.
Additional preliminary data suggest that proteasomal inhibition results in increased
abundance and activity of PPAR-gamma, which functions as an inhibitor of TGF-beta. We
hypothesize that the administration of proteasomal inhibitors prevents the
ubiquitin-mediated degradation of PPAR-Gamma in normal human lung fibroblasts and
in the mouse lung thereby inhibiting the transcriptional response to active TGF-beta
and attenuating fibrosis. We have generated three interrelated specific aims to identify
the molecular mechanisms by which PPAR-gamma is degraded and by which this degradation
is accelerated in the presence of TGF-beta. Aim 1. Is PPAR-gamma required for inhibition of
the transcriptional response to active TGF-beta induced by proteasomal inhibition in
normal human lung fibroblasts? Aim 2. How is PPAR-gamma targeted for proteasomal
degradation in normal human lung fibroblasts? Aim 3. Does the bortezomibmediated
increase in the protein abundance of PPAR-gamma prevent the development of
lung fibrosis in mice treated with bleomycin downstream of the activation of TGF-
beta1? This application represents a highly innovative effort that employs molecular tools in
cell culture systems and sophisticated mouse models to elucidate the mechanisms by
which proteasomal inhibition might prevent the development of pulmonary fibrosis. Our
preliminary data support the feasibility of the proposed experiments and provide support
for our focus on the ubiquitin-proteasomal system’s regulation of PPAR-gamma.
Effective start/end date10/1/125/31/15


  • Jesse Brown VA Medical Center (Agreement Date: 11/8/13)


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