NORMAL SKIN LIPID METABOLISM & CORNIFICATION DISORDERS

正常皮肤脂质代谢

• 批准号: 3155724
• 负责人: MARY L WILLIAMS
• 金额: $ 15.89万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-07-01 至 1992-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3155724
• 关键词: alcohols; alkanes; blood lipoprotein metabolism; catalase; fatty acid metabolism; fibroblasts; hairless mouse; hereditary carnitine deficiency myopathy; histochemistry /cytochemistry; human tissue; keratinization; laboratory mouse; laboratory rat; lipid biosynthesis; lipid metabolism; molecular pathology; organelles; oxidation reduction reaction; peroxisome; phospholipase C; plasminogen; radiotracer; skin; tissue /cell culture; triacylglycerol lipase; triglycerides

In mammalian skin, permeability barrier function and desquamation are mediated by intercellular stratum corneum lipids. The metabolic pathways whereby epidermis generates lipid for these stratum corneum functions is not well-understood, however, several inherited skin diseases characterized by abnormal desquamation and associated with discrete lipid metabolic defects provide models for the study of these pathways. Some diseases are characterized by accumulation of very long chain (v.l.c.) n-alkanes, also found in normal skin. These studies are based upon the hypothesis that epidermis synthesizes alkanes from fatty acids or alcohols; that changes in the number or function of peroxisomes, a cellular organelle involved in fatty alcohol and v.l.c. fatty acid metabolism, are involved in n-alkane accumulation in outer epidermis; and that delineation of the underlying defect in neutral lipid storage disease (NLSDI), where triglycerides accumulate in viable cells, but alkanes accumulate in stratum corneum, will further illuminate the origin of epidermal alkanes. The defect in NLSDI is postulated to be an intercellular triacylglycerol lipase that generates diacylglycerols for phospholipid biosynthesis. Evidence for alkane biosynthesis will be sought using radiolabelled v.l.c. fatty acids in cultured human keratinocytes (CHK), rodent epidermis in vivo, and in mutant fibroblasts and products analyzed by radiochemical GLC. The relationship of alkane synthesis to differentiation will be assessed in isolated epidermal layers and in CHK cultured by a variety of methods designed to alter differentiation. Peroxisomes will be quantitated in relation to differentiation by ultrastructural cytochemistry for catalase and by three functional assays for peroxisome specific pathways in both CHK and rodent epidermis. The cause of NLSDI will be probed in three NLSDI fibroblast cell lines using radiolabelled precursors and by measurement of pool size using recombinant diacylglycerol kinase. Delineation of the metabolic defect in NLSDI will contribute to our understanding of glycerolipid metabolism and to the origin of epidermal alkanes. Studies with mutant cells which exhibit defects in v.l.c. fatty acid oxidation will aid in our understanding of the role of peroxisomes in normal epidermal lipid metabolism.

在哺乳动物皮肤中，通透性屏障功能和脱屑是 由细胞间角质层脂质介导。代谢途径 因此，表皮为角质层的这些功能产生脂质 然而，人们对几种遗传性皮肤病的特征并不了解 由异常脱屑引起，并与离散的脂代谢有关 缺陷为研究这些途径提供了模型。有些疾病是 以积累很长的链(v.l.c.)为特征正构烷烃，也是 在正常皮肤中发现。这些研究是基于这样一个假设： 表皮从脂肪酸或酒精中合成烷烃；这在 过氧化物体的数量或功能，它是一种细胞细胞器，参与 脂肪酒精和v.l.c。脂肪酸代谢，都与正构烷烃有关 在外表皮中堆积；以及底层的描绘 中性脂肪堆积症(NLSDI)的缺陷，其中甘油三酯 在活细胞中积累，但烷烃在角质层积累，将 进一步阐明了表皮烷烃的来源。NLSDI的缺陷是 被认为是一种细胞间三酰甘油脂肪酶，它能产生 用于磷脂生物合成的二酰基甘油。烷烃的证据 将使用放射性标记的v.l.c寻求生物合成。人体内的脂肪酸 培养的人角质形成细胞(CHK)，啮齿动物表皮，体内和突变体 成纤维细胞及其产物的放射化学气相色谱分析。两国关系 烷烃合成到分化的关系将在分离的 表皮层和在CHK中培养的各种方法设计 改变差异化。过氧酶体的数量将与以下各项相关 过氧化氢酶和三种酶的超微结构细胞化学鉴别 CHK和啮齿动物体内过氧化物酶体特异性通路的功能分析 表皮。将在三个NLSDI成纤维细胞中探讨NLSDI的原因 使用放射性标记前体和通过测量池大小的细胞系 使用重组二酰甘油激活剂。新陈代谢的描述 NLSDI的缺陷将有助于我们对甘油脂的理解 新陈代谢和表皮烷烃的起源。关于突变体的研究 在v.l.c.中出现缺陷的细胞。脂肪酸氧化将有助于我们的 了解过氧酶体在正常表皮脂质中的作用 新陈代谢。