Role of the PPARb in epithelial cell proliferation

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): Since it was first identified as a member
of the peroxisome proliferator-activated receptors (PPARs) in 1994, specific
roles for the PPARI3 have remained elusive. Despite numerous roles elucidated
for the PPARa and PPARy that contribute to diseases including hyperlipidemias,
atherosclerosis, obesity, diabetes and cancer, the function of PPARb has
remained a mystery. The recent phenotypical description of a PPARb-null mouse
has provided the first direct, in vivo evidence that the PPARb is involved in
epithelial cell proliferation. Topical application of the tumor promoter TPA
causes enhanced epidermal cell proliferation in PPARb-null mice compared to
controls suggesting that the hyperplastic response induced by TPA is attenuated
by the PPARb. Further, the non-steroidal anti-inflammatory drug (NSAID),
sulindac, inhibits TPA-induced inflammation and epidermal hyperplasia in
wild-type mice and this effect is not found in similarly treated PPARb-null
mice. This suggests that the beneficial effects of sulindac are modulated by
the PPARb. The overall hypothesis of this proposal is that the PPARb3 is
central to the epithelial cell proliferative response that results in skin
tumor formation from genetic or chemical factors. A secondary hypothesis is
that PPARb-null mice will be refractory to the influence of sulindac in
preventing epidermal hyperplasia that contributes to skin tumor formation. The
first specific aim is to develop three model systems to test these hypotheses.
The first model will utilize crossing the PPARb-null mice with patched +1/-
mice that are genetically more sensitive to ultraviolet or ionizing
radiation-induced skin tumors. The second model will assess two-stage
carcinogenicity in the PPARb-null mouse and the last model will characterize a
keratinocyte culture system using cells from PPARb-null mice so that it can be
utilized to further mechanistically define the role of the PPARb in the
TPA-induced epidermal cell proliferative response. Since preliminary data
indicate that PPARb attenuates TPA-induced COX-2 mRNA expression, the second
specific aim will determine if PPARb-specific alterations in eicosanoid
function contribute to the mechanisms of enhanced epidermal cell proliferation.
The third specific aim will identify and initially characterize PPARbdependent
gene expression in skin cells resulting from treatment with TPA. Results from
this work will determine if PPARb influences epidermal cell proliferation that
contribute to the incidence of skin cancer, determine if PPARb-dependent
alterations in eicosanoid metabolism underlie enhanced cell proliferation
induced by TPA in PPARb-null mice, and characterize PPARb target genes in
epithelial cells.
StatusFinished
Effective start/end date6/15/015/31/06

Funding

  • National Cancer Institute: $211,530.00
  • National Cancer Institute: $246,024.00
  • National Cancer Institute: $173,231.00
  • National Cancer Institute: $238,121.00

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