Sphingolipid Metabolism and Signaling in the Retina

视网膜中的鞘脂代谢和信号传导

• 批准号: 8449084
• 负责人: Nawajes Mandal
• 金额: $ 35.15万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8449084
• 关键词: Adhesions; Age; Age related macular degeneration; Anabolism; Apoptosis; Apoptotic; Area; Biochemical; Biological Assay; Blindness; Caspase-1; Cell Death; Cell Survival; Cell physiology; Cells; Ceramidase; Ceramides; Cessation of life; Data; Degenerative Disorder; Development; Diabetes Mellitus; Diabetic Retinopathy; Disease; Embryo; Enzymes; Equilibrium; Excision; Family; Feedback; Gene Mutation; Genes; Genetic; Genetic Models; Genetic Variation; Goals; Homeostasis; Human; Immune; Infiltration; Inflammation; Inherited; Injection of therapeutic agent; Knockout Mice; Light; Lipid Bilayers; Measures; Mediator of activation protein; Membrane Lipids; Membrane Microdomains; Metabolism; Modeling; Mutation; Nerve Degeneration; Pathway interactions; Photoreceptors; Physiological; Physiology; Pilot Projects; Play; Process; Production; Rattus; Receptor Gene; Regulation; Reporting; Research; Retina; Retinal; Retinal Degeneration; Retinal Dystrophy; Retinitis Pigmentosa; Rodent Model; Role; Signal Transduction; Sphingolipids; Sphingomyelinase; Sphingosine; Sphingosine-1-Phosphate Receptor; Stress; Structure; Structure of retinal pigment epithelium; T-Lymphocyte; Testing; Therapeutic; Therapeutic Intervention; Transgenic Organisms; Vascular Endothelial Cell; abstracting; albino rat; analog; ceramide 1-phosphate; edg-1 Protein; efficacy testing; fluidity; galactosylgalactosylglucosylceramidase; human disease; in vivo; inhibitor/antagonist; inorganic phosphate; migration; mouse model; neovascularization; new therapeutic target; novel; research study; retinal rods; sphingosine 1-phosphate; sphingosine kinase; tumorigenesis

Project Summary/Abstract: Sphingolipids are a family of membrane lipids with important structural roles in the regulation of the fluidity and subdomain structure of the lipid bilayer, especially lipid rafts. Ceramide (Cer) is the key metabolite for all sphingolipid biosynthesis. Cer and its metabolite sphingosine-1-phosphate (S1P) are signaling sphingolipids; implicated in several human diseases associated with inflammation, tumorigenesis, diabetes, and neurodegeneration. Cer signals primarily for apoptosis, whereas S1P has an opposing intracellular role in cell survival. S1P also signals paracellularly via its receptors (S1P1-5), which are mostly present in vascular endothelial cells and T cells and signals for adhesion, migration, inflammation, and neovascularization. Consistent with its role in apoptosis, ceramide has recently been shown to be involved in photoreceptor cell death. Our preliminary data show ceramide levels are increased during retinal degeneration in several models of inherited and stress-induced retinal degeneration. We also observed increased S1P levels and expression in degenerating retinas. S1P is known to have inhibitory effect on ceramide synthesis. In pilot studies, we determined that S1P is a competitive inhibitor of sphingomyelinase (SMase) also, another group of enzymes responsible for ceramide production in cells, suggesting a role for S1P in the regulated feedback of Cer production. When we injected Cer into the rat vitreous, we observed severe inflammation followed by loss of retinal function and photoreceptor cell death. We further found that FTY720, a de novo Cer synthesis inhibitor, blocked Cer production in the rat retina and protected rods from light-induced degeneration. Our preliminary results show an active sphingolipid metabolism in the retina and suggest that the delicate balance between ceramide and S1P is important in maintaining normal retinal structure and function. In this proposal we will test the hypothesis that the dysregulated balance between Cer and S1P in the retina leads to retinal inflammation and cell death. The experiments proposed in four specific aims will focus on elucidating the physiological role of Cer in retinal degenerative diseases, understanding how Cer levels are regulated, exploring the therapeutic potential of inhibitors that target Cer synthesis or the enzymes that can degrade Cer, determining how S1P is related to Cer metabolism in the retina, and how important is the balance of Cer and S1P in maintaining retinal homeostasis and function. This proposal will explore the role of Ceramide and S1P in retinal physiology and diseases. This is a novel and underserved area of retinal research and has relevance to many forms of human retinal dystrophies including age-related macular degeneration, diabetic retinopathy, and retinitis pigmentosa. Mechanistic studies will likely identify novel pathways and novel targets for therapeutic intervention.

项目摘要/摘要： 鞘磷脂是一类膜脂类化合物，具有重要的结构作用。 脂双层，尤其是脂筏的流动性和亚区结构。神经酰胺(Ceramide，Cer)是人体的关键代谢产物 用于所有鞘脂的生物合成。CER及其代谢物鞘氨醇-1-磷酸(S1P)是信号转导 鞘脂；与多种人类疾病有关，与炎症、肿瘤发生、糖尿病、 和神经退化。CER信号主要用于细胞凋亡，而S1P在细胞内具有相反的作用 细胞存活。S1P也通过其受体(S1P1-5)发出细胞旁信号，这些受体主要存在于血管中 内皮细胞和T细胞以及黏附、迁移、炎症和新生血管的信号。 神经酰胺与其在细胞凋亡中的作用相一致，最近被证明与光感受器细胞有关。 死亡。我们的初步数据显示，在几个模型中，神经酰胺水平在视网膜变性期间升高。 遗传性和应激性视网膜变性。我们还观察到S1P水平和表达在 退化的视网膜。已知S1P对神经酰胺的合成有抑制作用。在试点研究中，我们 确定S1P是鞘磷脂酶(SMase)的竞争性抑制物，也是另一组酶 负责细胞内神经酰胺的产生，提示S1P在Cer的调节反馈中发挥作用 制作。当我们将Cer注射到大鼠玻璃体中时，我们观察到严重的炎症随后失去 视网膜功能和感光细胞死亡。我们进一步发现，FTY720是一种从头合成的Cer合成抑制剂， 阻断大鼠视网膜中Cer的产生，保护视杆细胞免受光诱导的变性。我们的预赛 结果显示，视网膜中的鞘磷脂代谢活跃，这表明 神经酰胺和S1P对维持正常的视网膜结构和功能很重要。在本提案中，我们将测试 视网膜中Cer和S1P之间的失衡导致视网膜的假说 炎症和细胞死亡。在四个具体目标中提出的实验将集中于阐明 Cer在视网膜退行性疾病中的生理作用，了解Cer水平是如何调节的， 探索靶向Cer合成的抑制剂或能降解Cer的酶的治疗潜力， 确定S1P如何与Cer在视网膜中的代谢有关，以及Cer和Cer的平衡有多重要 S1P在维持视网膜动态平衡和功能方面的作用。 这项建议将探讨神经酰胺和S1P在视网膜生理和疾病中的作用。这是一个 视网膜研究的新领域，与多种形式的人类视网膜营养不良有关 包括老年性黄斑变性、糖尿病视网膜病变和视网膜色素变性。机械学研究 将可能为治疗干预确定新的途径和新的靶点。