EFFECT OF PPAR-ALPHA ACTIVATORS ON KERATINOCYTE DIFFERENTIATIION

表皮的主要功能是在外部环境和机体之间提供屏障，为了实现这一功能，角质形成细胞经历了复杂的分化途径，最终形成角质层（SC）的角化和细胞外脂质富集膜。这一过程的调控尚不清楚，但亲脂化合物，如类维生素a和维生素D，它们与核激素受体相互作用，起着重要作用。我们最近的研究表明，核激素受体家族成员pparα的激活可以调节角质形成细胞的分化。我们已经证明1)pparα配体加速了胚胎大鼠SC细胞外脂质富集膜的发育，2)pparα配体增加了胚胎表皮中两种脂质代谢酶的活性，这两种酶对SC的形成和功能至关重要：-葡萄糖脑苷酶和类固醇硫酸酯酶。3) pparα配体增加胎儿表皮中聚丝蛋白和loricrin mRNA和蛋白的表达；4)pparα配体增加培养的人角质形成细胞中天合蛋白和转谷氨酰胺酶1 mRNA和蛋白的表达。这些结果表明，用ppar配体处理会影响末端分化的几个关键成分。假设：ppar配体刺激角质细胞/表皮分化。目的1：确定在培养的人角质形成细胞中，ppar配体是否诱导了对角质形成细胞分化重要的结构蛋白的表达，并确定这种增加的机制。目的3：利用PPARalpha敲除小鼠，确定PPARalpha在调节培养小鼠角质形成细胞和完整表皮结构蛋白和脂质酶表达中的重要性。

The major function of the epidermis is to provide a barrier between the external environment and the organism To fulfill this function keratinocytes undergo a complex pathway of differentiation which culminates in cornification and the formation of extracellular lipid enriched membranes in the stratum corneum (SC). The regulation of this process is not well understood but lipophilic compounds, such as retinoids and vitamin D, which interact with nuclear hormone receptors play an important role. We have recently shown that activation of PPARalpha, a member of the nuclear hormone receptor family, regulates keratinocyte differentiation. We have shown 1) that PPARalpha ligands accelerates the development of the extracellular lipid enriched membranes in the SC of fetal rats, 2) that PPARalpha ligands increase the activity in fetal epidermis of two lipid metabolic enzymes essential for formation and function of the SC. beta- glucocerebrosidase, and steroid sulfatase, 3) that PPARalpha ligands increase filaggrin and loricrin mRNA and protein expression in fetal epidermis and 4) that PPARalpha ligands increase mRNA and protein levels of involucrin and transglutaminase 1 in human keratinocytes in culture. These results demonstrate that treatment with PPARalpha ligands affects several key components of terminal differentiation. Hypothesis: That PPARalpha ligands stimulate keratinocyte/epidermal differentiation. Aim 1: To determine in human keratinocytes in culture if PPARalpha ligands induce the expression of structural proteins important for keratinocyte differentiation and determine the mechanisms for this increase. Aim 3: Using PPARalpha Knockout mice determine the importance of PPARalpha in regulating the expression of structural proteins and lipid enzymes in culture mouse keratinocytes and in intact epidermis.