REGULATION OF EPIDERMAL LIPID METABOLISM

表皮脂质代谢的调节

• 批准号: 2442808
• 负责人: KENNETH R FEINGOLD
• 金额: $ 20.45万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-01-10 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2442808
• 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

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：（改编自申请人的摘要）- 之前的研究 已证明屏障破坏后可修复； 1） 需要表皮脂质合成，2) 与 LDL 增加相关 受体和载脂蛋白 E 水平，表明脂质的摄取可能 也很重要，3）表皮的钙含量很重要 其屏障形成的调节器。 将测试三个假设。 假设 1 - 脂质的摄取 角质形成细胞在屏障稳态中起着重要作用，并且这 摄取由 LDL 受体介导，并通过增加表达来促进 表皮中的 LDL 受体、apo E 和 LCAT。 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 LDL 受体和 apo E 增加的位置 屏障破坏后，2) 确定 LDL 受体或 apo E 缺陷会损害 LDL 和 apo E 敲除小鼠的屏障修复，3) 确定 LCAT 活性是否在屏障破坏后受到刺激， 如果抑制 LCAT 活性会损害屏障稳态，并且 4) 确定循环脂蛋白是否在其中起重要作用 为屏障稳态提供脂质。 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 导致表皮脂质代谢的改变，这是至关重要的 用于屏障稳态。 这个假设将通过两个特定的 目标； 1）判断表皮钙含量是否变化 调节脂质代谢，2) 确定钙的吸收是否进入 细胞影响脂质代谢。 第三个假设是，改变 屏障破坏诱导的脂质代谢在 通过甾醇调节元件结合的基因转录水平 蛋白质（SREBP）。 这将通过三个具体目标进行测试； 1）确定 如果屏障破坏导致蛋白质 mRNA 水平增加 受 SREBP 协调调节，2) 确定 25-羟基是否 胆固醇可抑制活性 SREBP 的形成，从而阻断 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。