EFFECT OF PPAR-ALPHA ACTIVATORS ON KERATINOCYTE DIFFERENTIATIION

表皮的主要功能是在外部环境和生物体之间提供屏障，以实现这一功能。角质形成细胞经历了一条复杂的分化途径，最终导致角质化，并在角质层形成细胞外富脂膜。这一过程的调节机制还不是很清楚，但与核激素受体相互作用的亲脂化合物，如维甲酸和维生素D，发挥了重要作用。我们最近发现，核激素受体家族成员PPARpha的激活调节角质形成细胞的分化。结果表明：1)PPARpha配体促进胎鼠SC细胞外富脂膜的形成；2)PPARpha配体增加胎鼠SC形成和功能所必需的两种脂代谢酶的活性。β-葡萄糖脑苷酶和类固醇硫酸酯酶，3)PPARpha配体增加胎儿表皮微丝蛋白和氯丙蛋白的mRNA和蛋白表达，4)PPARpha配体增加培养的人角质形成细胞中总蛋白和转谷氨酰胺酶1的mRNA和蛋白水平。这些结果表明，用PPARpha配体处理会影响末端分化的几个关键成分。假设：PPARpha配体刺激角质形成细胞/表皮分化。目的1：在体外培养的人角质形成细胞中，确定PPARpha配体是否诱导角质形成细胞分化所必需的结构蛋白的表达，并确定其上调的机制。目的：利用PPARpha基因敲除小鼠，确定PPARpha在调节培养的小鼠角质形成细胞和完整表皮中结构蛋白和脂酶表达的重要性。

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.