REGULATION OF EPIDERMAL LIPID METABOLISM

描述：（改编自申请人摘要）-既往研究 已经证明屏障破坏后的修复; 1） 需要表皮脂质合成，2）与LDL增加有关 受体和载脂蛋白E水平，表明脂质的摄取可能 也是重要的，3）表皮的钙含量是一个重要的 它们屏障形成的调节器。 将检验三个假设。 假设1 -脂质的摄取 角质形成细胞在屏障稳态中起重要作用， 摄取由LDL受体介导，并通过表达增加而促进 低密度脂蛋白受体，载脂蛋白E，和LCAT在表皮。 这一假设将通过四个具体目标进行检验。 具体目标一是 以确定LDL受体和载脂蛋白E增加的位置， 在屏障破坏后，2）确定LDL受体或载脂蛋白E 使用LDL和apo E敲除小鼠，缺乏损害屏障修复，3） 确定屏障破坏后LCAT活性是否被刺激， 以及如果LCAT活性的抑制损害屏障稳态，以及4） 确定循环脂蛋白是否在 为屏障内环境稳定提供脂质。 第二个假设是， 屏障的破坏改变了钙的分布和浓度 钙浓度的变化是一种信号 导致表皮脂质代谢的改变， 屏障内稳态 这一假设将由两个具体的 目的：1）确定表皮中钙含量的变化 调节脂质代谢，和2）确定钙的摄取是否进入 细胞影响脂质代谢。 第三个假设是， 由屏障破坏诱导的脂质代谢是协调调节的， 固醇调节元件结合基因转录水平 蛋白质（SREBP）。 这将通过三个具体目标进行测试：1）确定 如果屏障破坏诱导蛋白质的mRNA水平增加， 由SREBP协调调节，2）确定25-羟基 胆固醇抑制活性SREBP的形成， mRNA水平的增加，以及3）确定SREBP的活性形式是否是 由屏障破坏引起的。

DESCRIPTION: (Adapted from the applicant's abstract) - Previous studies have demonstrated that repair of barrier following its disruption; 1) requires epidermal lipid synthesis, 2) is associated with increased LDL receptor and apolipoprotein E level, suggesting that uptake of lipids may also be important, and 3) calcium content of the epidermis is an important regulator of their barrier formation. Three hypotheses will be tested. Hypothesis 1 - That the uptake of lipid by keratinocytes plays an important role in barrier homeostasis and that this uptake is mediated by LDL receptor and facilitated by increased expression of LDL receptor, apo E, and LCAT in the epidermis. This hypothesis will be tested by four specific aims. Specific aim one is to determine the location of the increase in LDL receptors and apo E following barrier disruption, 2) determine whether LDL receptor or apo E deficiency impairs barrier repair using LDL and apo E knockout mice, 3) determine whether LCAT activity is stimulated following barrier disruption, and if inhibition of LCAT activity impairs barrier homeostasis, and 4) determine whether circulating lipoproteins play an important role in providing lipids for barrier homeostasis. The second hypothesis is that disruption of barrier alters the distribution and concentration of calcium in the epidermis, and that changes in calcium concentrations is a signal that causes alterations in epidermal lipid metabolisms, which are essential for barrier homeostasis. This hypothesis will be tested by two specific aims; 1) determine whether changes in calcium content in the epidermis regulate lipid metabolism, and 2) determine if the uptake of calcium into cells affects lipid metabolism. The third hypothesis is that alterations in lipid metabolism induced by barrier disruption are coordinately regulated at the level of gene transcription by sterol regulatory element binding proteins (SREBPs). This will be tested by three specific aims; 1) determine if barrier disruption induces an increase in mRNA levels of proteins that are coordinately regulated by SREBPs, 2) determine if 25-hydroxy cholesterol, which inhibits the formation of active SREBPs, blocks the increase in mRNA levels, and 3) determine if the active form of SREBPs is induced by barrier disruption.