权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

REGULATION OF EPIDERMAL LIPID METABOLISM

表皮脂质代谢的调节

基本信息

批准号：
6029954
负责人：
KENNETH R FEINGOLD
金额：
$ 22.12万
依托单位：
NORTHERN CALIFORNIA INSTITUTE/RES/EDU
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-01-10 至 2001-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6029954
关键词：
apolipoprotein E calcium flux gene targeting genetic transcription hydroxycholesterols keratinocyte laboratory mouse lipid metabolism lipogenesis inhibitor low density lipoprotein receptor membrane lipids membrane permeability phosphatidylcholine sterol acyltransferase skin skin absorption

项目摘要

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.

描述：(改编自申请者的摘要)-以前的研究已证明障碍物在中断后进行了修复；1) 需要表皮脂肪合成，2)与增加的低密度脂蛋白有关受体和载脂蛋白E水平，提示脂质的摄取可能也是重要的，而3)表皮的钙含量是一个重要的它们的屏障形成的调节器。三个假说将被检验。假设1--人体对脂肪的吸收角质形成细胞在屏障动态平衡中起着重要作用低密度脂蛋白受体介导摄取并通过增加表达促进摄取低密度脂蛋白受体、载脂蛋白E和LCAT在表皮中的表达。这一假设将通过四个具体目标进行检验。具体目标一是确定低密度脂蛋白受体和载脂蛋白E升高的部位屏障破坏后，2)确定低密度脂蛋白受体或载脂蛋白E 缺陷损害低密度脂蛋白和载脂蛋白E基因敲除小鼠的屏障修复，3) 确定LCAT活性在屏障破坏后是否受到刺激，如果LCAT活性的抑制损害了屏障的稳态，以及4) 确定循环脂蛋白是否在为屏障动态平衡提供脂质。第二个假设是屏障的破坏改变了钙的分布和浓度在表皮中，钙浓度的变化是一个信号这会引起表皮脂代谢的改变，这是必不可少的来维持屏障内环境平衡。这一假设将通过两个具体的目的：1)确定表皮中钙含量的变化调节脂质代谢，以及2)确定钙的吸收是否进入细胞影响脂类代谢。第三个假设是，屏障破坏诱导的脂质代谢在血管内皮细胞固醇调节元件结合对基因转录水平的影响蛋白质(SREBPs)。这将通过三个具体目标来检验：1)确定如果屏障的破坏导致蛋白质的mRNA水平增加，受SREBPs协调调节，2)确定25-羟基胆固醇抑制活性SREBPs的形成，阻止 MRNA水平的增加，以及3)确定SREBPs的活性形式是否由障碍物破坏引起。