Evaluation of peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta) behavior in skin repair and its modulation by ligands

Abstract

The Peroxisome Proliferator-activated Receptor beta/delta (PPAR²) is a transcription factor, member of the nuclear receptor's superfamily. This protein can be found in several human tissues, mainly in those involved in high lipid metabolism and dependent on cell proliferation and differentiation, such as skin, intestine, placenta, adipose tissue, brain and skeletal muscle. PPAR² heterodimerizes with the Retinoid X Receptor (RXR). Upon ligand binding, the heterodimer can activate transcription of target genes through coactivator recruitment into promoter regions. An example of gene which expression is regulated by PPAR² is the cytokine Transforming Growth Factor B1 (TGF B1) gene. This cytokine regulates the expression of proteins important in maintaining skin structure, such as type I collagen, matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). The unbalance of collagen, MMPs and TIMPs production is one of the major factors that prompt skin aging and wrinkling, due to structural disorganization that this unbalance causes in the tissue. Previous studies showed the PPAR² role on skin repair, collagen production and stratum corneum revitalization. The goal of my project is to extend this knowledge by screening for PPAR² activators able to promote repair and restore homeostasis. For this purpose, we intend to study, in human keratinocytes, PPAR² expression and activation by quantification of target genes. Then we also would like to study the effects of PPAR² activation on keratinocyte proliferation, migration and differentiation and wound healing models. The obtained information would contribute to the identification and development of new drug candidates targeting PPAR² in skin disorders Experiments will be carried out under the supervision of Dr. Liliane Michalik at the University of Lausanne, Switzerland. (AU)