Sphingolipid Metabolism and Signaling in the Retina

视网膜中的鞘脂代谢和信号传导

基本信息

项目摘要

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Retinal degeneration can cause vision loss at any age. The long-term goal of this project is to understand the role of sphingolipid metabolites that can initiate or potentiate retinal degeneration. This is important because identifying these specific mediators can provide novel targets for therapeutic manipulation to inhibit degeneration.
描述(由申请人提供):鞘脂是膜脂质家族,在调节脂双层(尤其是脂筏)的流动性和亚结构域结构中具有重要的结构作用。神经酰胺(Cer)是所有鞘脂生物合成的关键代谢产物。Cer及其代谢产物鞘氨醇-1-磷酸(S1 P)是信号鞘脂;与炎症、肿瘤发生、糖尿病和神经变性相关的几种人类疾病有关。Cer信号主要用于细胞凋亡,而S1 P在细胞存活中具有相反的细胞内作用。S1 P还通过其受体(S1 P1 -5)进行细胞旁信号传导,所述受体主要存在于血管内皮细胞和T细胞中,并且是粘附、迁移、炎症和新血管形成的信号。与其在细胞凋亡中的作用一致,神经酰胺最近已被证明参与感光细胞死亡。我们的初步数据显示,在几种遗传性和应激诱导的视网膜变性模型中,神经酰胺水平在视网膜变性期间增加。我们还观察到在退化的视网膜中S1 P水平和表达增加。已知S1 P对神经酰胺合成具有抑制作用。在初步研究中,我们确定S1 P也是鞘磷脂酶(SMase)的竞争性抑制剂,SMase是另一组负责细胞中神经酰胺生产的酶,这表明S1 P在Cer生产的调节反馈中发挥作用。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,随后视网膜功能丧失和感光细胞死亡。我们进一步发现,FTY 720,一种从头Cer合成抑制剂,阻断大鼠视网膜中Cer的产生,并保护视杆免受光诱导的变性。我们的初步研究结果表明,在视网膜鞘脂代谢活跃,并建议神经酰胺和S1 P之间的微妙平衡是重要的,在维持正常的视网膜结构和功能。在这项提案中,我们将测试视网膜中Cer和S1 P之间的平衡失调导致视网膜炎症和细胞死亡的假设。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水平如何调节,探索靶向Cer合成或可以降解Cer的酶的抑制剂的治疗潜力,确定S1 P如何与视网膜中的Cer代谢相关,以及Cer和S1 P的平衡在维持视网膜稳态和功能中的重要性。 该提案将探讨神经酰胺和S1 P在视网膜生理和疾病中的作用。这是视网膜研究的一个新的和服务不足的领域,并与许多形式的人类视网膜营养不良,包括年龄相关性黄斑变性,糖尿病视网膜病变,视网膜色素变性。机制研究可能会发现新的途径和新的治疗干预的目标。 公共卫生相关性:视网膜变性可导致任何年龄的视力丧失。该项目的长期目标是了解鞘脂代谢物的作用,可以启动或加强视网膜变性。这是重要的,因为识别这些特定的介质可以提供新的治疗操纵,以抑制变性的目标。

项目成果

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Nawajes Mandal其他文献

Nawajes Mandal的其他文献

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{{ truncateString('Nawajes Mandal', 18)}}的其他基金

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
  • 财政年份:
    2012
  • 资助金额:
    $ 37万
  • 项目类别:
Sphingolipid Metabolism and Signaling in the Retina
视网膜中的鞘脂代谢和信号传导
  • 批准号:
    8634101
  • 财政年份:
    2012
  • 资助金额:
    $ 37万
  • 项目类别:
Sphingolipid Metabolism and Signaling in the Retina
视网膜中的鞘脂代谢和信号传导
  • 批准号:
    8822296
  • 财政年份:
    2012
  • 资助金额:
    $ 37万
  • 项目类别:

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