PPARs and LXR Regulate Epidermal Differentiation

描述(由申请人提供)： 表皮面临着一项艰巨的任务，即产生一种渗透性屏障，使哺乳动物能够在干旱的陆地环境中生存。为了实现这一目标，表皮生成角质层(SC)，它具有高度疏水、富含脂肪的细胞外基质，组织成硬质角质细胞之间的板层双层。为了产生这些独特的保护结构，角质形成细胞必须合成大量的胆固醇、脂肪酸和神经酰胺，这些胆固醇、脂肪酸和神经酰胺以大约等摩尔的比例输送到SC，同时形成角质细胞，富含交联化的蛋白质形成角化的包膜。尽管产生这种功能性的两室干细胞非常重要，但协调调节角膜细胞和细胞外板层膜平行形成的机制仍然很大程度上是未知的。 我们的假设是，NHR脂敏剂(PPAR-α、-β/Delta、-Gamma和LXR)通过首先检测脂质水平，然后协调调节角质形成所需的结构蛋白和调节Cer/GIcCer合成的酶蛋白的表达，共同调节角质形成细胞的分化，从而调控角质形成细胞的分化。 我们建议确定：1)激活PPAR-α、-β、-γ和LXR是否刺激Cer/GIcCer合成/板层小体形成和角质细胞形成；2)PPAR和LXR激活刺激角质细胞蛋白质表达的分子机制；3)PPAR和LXR激活剂上调Cer/GIcCer产生的分子机制；以及4)评估脂质和蛋白质的产生是否进一步协调，使得FA和/或Chol合成的波动协调调节角质细胞蛋白质的产生；即表征表皮分化的脂质和蛋白质合成的整合。 由于角化和形成表皮屏障脂类，以及随后的细胞外片层的生成，是表皮分化的后期步骤，所提出的研究将导致关于成熟SC生成和表皮动态平衡的协调调节的重要新信息。

DESCRIPTION (provided by applicant): The epidermis is faced with the daunting task of generating a permeability barrier that allows survival of mammals in a xeric, terrestrial environment. To accomplish this goal, the epidermis generates the stratum corneum (SC), with its highly hydrophobic, lipid-enriched extracellular matrix, organized into lamellar bilayers between rigid corneocytes. To generate these unique protective structures, keratinocytes must synthesize extensive quantities of cholesterol, fatty acids, and ceramides, delivered in an approximately equimolar ratio to the SC, simultaneous with formation of corneocytes, enriched in proteins that are crosslinked to form the cornified envelope. Despite the critical importance of generating this functional, two-compartment SC, the mechanisms that coordinately regulate the parallel formation of corneocytes and the extracellular lamellar membranes remain largely unknown. It is our hypothesis that NHR liposensors (PPAR-alpha, -beta/ delta, -gamma, and LXR) regulate keratinocyte differentiation by first sensing lipid levels, and then coordinately regulating the expression of structural proteins required for corneocyte formation and enzyme proteins that regulate Cer/ GIcCer synthesis, together leading to formation of a functional SC. We propose to determine: 1) whether activation of PPAR-alpha, -delta, and -gamma, and LXR stimulate Cer/ GIcCer synthesis/ lamellar body formation and corneocyte formation; 2) the molecular mechanisms by which activation of PPARs and LXR stimulate expression of corneocyte proteins; 3) the molecular mechanisms by which activators of PPARs and LXR upregulate Cer/ GIcCer production; and finally, 4) to assess whether lipid and protein production are further co-ordinated, such that fluctuations in FA and/ or Chol synthesis co-ordinately regulate corneocyte protein production; i.e., the integration of lipid and protein syntheses that characterizes epidermal differentiation. Since cornification and formation of epidermal barrier lipids, with subsequent generation of the extracellular lamellae, are late steps in epidermal differentiation, the proposed studies will result in significant new information regarding the coordinate regulation of mature SC generation and epidermal homeostasis.