Role of the PPARb in epithelial cell proliferation

Project: Research project

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 Institutes of Health: $211,530.00
  • National Institutes of Health: $246,024.00
  • National Institutes of Health: $173,231.00
  • National Institutes of Health: $238,121.00

Fingerprint

Epithelial Cells
Cell Proliferation
Sulindac
Skin
Eicosanoids
Hyperplasia
Neoplasms
Null Lymphocytes
Peroxisome Proliferator-Activated Receptors
Skin Neoplasms
Ionizing Radiation
Hyperlipidemias
Keratinocytes
Carcinogens
Atherosclerosis
Anti-Inflammatory Agents
Obesity
Inflammation
Gene Expression
Messenger RNA