Epidermal Mechanisms Opposing Ceramide-Induced Apoptosis

表皮机制对抗神经酰胺诱导的细胞凋亡

基本信息

批准号：
7169801
负责人：
YOSHIKAZU UCHIDA
金额：
$ 30.98万
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：
2005
资助国家：
美国
起止时间：
2005-01-01 至 2009-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7169801
关键词：
Abbreviations Acylation Adverse effects Affect Antioxidants Apoptosis Apoptosis Inhibitor Apoptotic Appendix Ascorbic Acid B-Cell Lymphomas BIR Domain Back Carotenoids Caspase Catabolism Cell Death Cell Differentiation process Cell physiology Cells Ceramidase Ceramide glucosyltransferase Ceramides Chemicals Class Cutaneous Data Disease Disruption Distal Elevation Encapsulated Environment Environmental Pollutants Enzymes Epidermis Event Excision Exposure to Extracellular Domain Extracellular Space Family Figs - dietary Generations Glucosylceramides Harlequin Ichthyosis Homeostasis Human Hydrolysis In Vitro Induction of Apoptosis Inflammatory Interleukin-16 Lipids Maintenance Mechanics Mediating Melanoma Cell Membrane Messenger RNA Metabolic Metabolic Pathway Metabolism Modification Mus Natural regeneration Necrosis Nitrogen Organelles Oxidants Oxidative Stress Oxidoreductase Ozone Pathogenesis Pathway interactions Penetration Permeability Peroxidase Peroxidases Phosphorylation Phosphotransferases Physiological Physiological Processes Premature aging syndrome Principal Investigator Production Protein Family Protein Isoforms Protein Overexpression Proteins Radiation, Other Rate Reduced Glutathione Regulation Relative (related person)Research Personnel Resistance Risk Role Signal Transduction Sphingolipids Sphingomyelinase Sphingomyelins Sphingosine Stratum corneum Superoxide Dismutase System Tissues Toxin Ultraviolet Rays Uric Acid Water Weight Xenobiotics alpha Tocopherol alveolar lamellar body bcl-xlong protein catalase cell type ceramide kinase chemotherapeutic agent enzyme activity extracellular glucosylceramidase human BCL2L1 protein human BIRC3 protein human BIRC4 protein in vivo inhibitor/antagonist irradiation keratinocyte kidney cell knockout gene leukemia malignant breast neoplasm member neoplastic cell phosphoethanolamine prevent programs response skin disorder sphingosine 1-phosphate sphingosine kinase stressor theories ultraviolet

项目摘要

DESCRIPTION (provided by applicant): Mammalian epidermis is poised at the interface with the environment, and it must both prevent excess transcutaneous water loss in a desiccating terrestrial environment, and protect underlying tissues from toxic mechanical and chemical insults. In addition to blocking the penetration of xenobiotics and chemical toxins, it mitigates the adverse effects of ultraviolet radiation and other form of oxidative stress (OS). Ceramide (Cer), as members of the nitrogen-containing lipid class (sphingolipids), represent one of the primary lipid constituents of the outermost layer of the epidermis, the stratum corneum, in which this critical permeability/xenobiotic/ antioxidant barrier resides. In addition to their critical role as bulk membrane constituents in barrier function, various Cer metabolites also have emerged as critical for numerous other cellular functions. Pertinently, OS from a variety of stressors increases cellular Cer levels, thereby triggering increased (potentially premature) apoptosis, and excessive apoptosis or premature differentiation can impact epidermal function negatively. It is our hypothesis that epidermal keratinocytes deploy two classes of protective mechanisms that restrict levels of intracellular Cer, both from the ever-present risk of exposure to oxidative stressors, and from the high levels of Cer production required to meet barrier requirements during epidermal differentiation: 1) distal metabolism/catabolism of excess Cer to non-apoptotic metabolites; and 2) rapid sequestration/externalization of Cer, as glucosylceramide and sphingomyelin precursors, within the epidermal lamellar body secretory system. In our first aim, we will delineate the mechanisms that protect keratinocytes from Cer generated in response to oxidative stress. In our second aim, we will determine the mechanisms that protect the epidermis from upregulated Cer production for maintenance of the permeability barrier. Because epidermis is inherently at higher potential risk than other tissues, due to its exposure to external oxidative stressors, and because it generates abundant amounts of Cer for the epidermal barrier, it is important to understand those mechanism(s) that regulate intracellular Cer levels, thereby protecting epidermis from premature Cer-induced apoptosis.

描述（由申请人提供）：哺乳动物表皮处于与环境的交界处，它必须既防止干燥的陆地环境中过多的经皮水分流失，又保护下面的组织免受有毒的机械和化学损伤。除了阻止外源物质和化学毒素的渗透外，它还能减轻紫外线辐射和其他形式的氧化应激 (OS) 的不利影响。神经酰胺 (Cer) 作为含氮脂质类（鞘脂）的成员，代表表皮最外层（角质层）的主要脂质成分之一，这一关键的渗透性/外源性/抗氧化屏障就位于其中。除了在屏障功能中作为体膜成分的关键作用之外，各种 Cer 代谢物也对许多其他细胞功能至关重要。相应地，来自各种应激源的 OS 会增加细胞 Cer 水平，从而引发细胞凋亡增加（可能过早），而过度细胞凋亡或过早分化会对表皮功能产生负面影响。我们的假设是，表皮角质形成细胞部署两类保护机制来限制细胞内 Cer 的水平，既来自暴露于氧化应激源的始终存在的风险，又来自表皮分化过程中满足屏障要求所需的高水平 Cer 产生： 1)过量Cer向非凋亡代谢物的远端代谢/分解代谢；和 2) Cer作为葡萄糖神经酰胺和鞘磷脂前体在表皮层状体分泌系统内快速隔离/外化。在我们的第一个目标中，我们将描述保护角质形成细胞免受氧化应激产生的 Cer 影响的机制。在我们的第二个目标中，我们将确定保护表皮免受 Cer 生成上调的机制，以维持渗透性屏障。因为表皮本身就比其他组织具有更高的潜在风险，因为它暴露于外部氧化应激源，并且因为它为表皮屏障产生大量的 Cer，所以了解调节细胞内 Cer 水平的机制非常重要，从而保护表皮免受 Cer 诱导的过早细胞凋亡。