NORMAL SKIN LIPID METABOLISM & CORNIFICATION DISORDERS

正常皮肤脂质代谢

• 批准号: 3155725
• 负责人: MARY L WILLIAMS
• 金额: $ 16.52万
• 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/3155725
• 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.

在哺乳动物的皮肤中，渗透屏障功能和脱屑是不可或缺的。 由细胞间角质层脂质介导。 的代谢途径 表皮为这些角质层功能产生脂质， 然而，还没有很好地理解，几种遗传性皮肤病的特点是 通过异常脱屑和与离散脂质代谢相关 缺陷为研究这些途径提供了模型。 有些疾病是 特征在于非常长的链（v.l.c.）正构烷烃，也 在正常皮肤中发现。 这些研究是基于这样的假设， 表皮从脂肪酸或醇合成烷烃;在 过氧化物酶体的数量或功能， 脂肪醇和V.L.C.脂肪酸代谢，参与正烷烃 外表皮中的积累;以及 中性脂质沉积病（NLSDI）缺陷，其中甘油三酯 在活细胞中积累，但烷烃在角质层中积累， 进一步阐明了表皮烷烃的起源。 NLSDI的缺点是 假设是一种细胞间三酰甘油脂肪酶， 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.中脂肪酸 培养的人角质形成细胞（CHK），啮齿类动物表皮在体内，并在突变体 通过放射化学GLC分析成纤维细胞和产物。 的关系 烷烃合成分化将在隔离评估 表皮层和CHK培养的各种方法，旨在 改变分化。 过氧化物酶体将根据 过氧化氢酶的超微结构细胞化学和三种 CHK和啮齿动物中过氧化物酶体特异性途径的功能测定 表皮 本研究将在三个NLSDI成纤维细胞中探讨NLSDI的病因 使用放射性标记的前体和通过测量池大小的细胞系 使用重组二酰基甘油激酶。 代谢的描述 NLSDI中的缺陷将有助于我们理解甘油脂质 代谢和表皮烷烃的起源。 突变体研究 在V.L.C.中表现出缺陷的电池。脂肪酸氧化将有助于我们 了解过氧化物酶体在正常表皮脂质中的作用 新陈代谢.