Bioactive Sphingolipid enzymes as targets in inflammation

生物活性鞘脂酶作为炎症靶点

• 批准号: 8812714
• 负责人: Lina M OBEID
• 金额: --
• 依托单位: NORTHPORT VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8812714
• 关键词: Address; Adverse effects; Anti-Inflammatory Agents; Anti-inflammatory; Arthritis; Binding; Bone Marrow; Cardiovascular system; Cells; Ceramidase; Ceramides; Chronic; Colitis; Cyclooxygenase Inhibitors; Data; Disease; Enzymes; Epithelial; Epithelial Cells; Family; Funding; G-Protein-Coupled Receptors; Genes; Goals; Homologous Gene; Human; Human Cloning; Immune; In Vitro; Incidence; Inflammation; Inflammatory; Inflammatory Response; Knock-out; Laboratories; Lead; Malignant Neoplasms; Mediating; Metabolism; Modality; Modeling; Mus; Myelogenous; Myeloid Cells; PTGS2 gene; Pathway interactions; Process; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Publishing; Regulation; Rheumatoid Arthritis; Role; Saccharomyces cerevisiae; Scheme; Sphingolipids; Sphingosine; Sphingosine-1-Phosphate Receptor; Testing; Tissues; Transplantation; Tumor Necrosis Factor-alpha; cell type; galactosylgalactosylglucosylceramidase; in vivo; inhibitor/antagonist; member; mouse model; novel; patient population; public health relevance; sphingosine 1-phosphate; sphingosine kinase; therapeutic development; therapeutic target

DESCRIPTION (provided by applicant): The long-term goal of this project is to define the role of bioactive sphingolipid metabolizing enzymes in inflammation and to target these enzymes for novel anti- inflammatory therapy. The PI's laboratory has an established track record of expertise in sphingolipid metabolism and function. Studies from the previous funding period have led us into a novel exciting direction on the role and regulation of bioactive sphingolipid metabolizing enzymes in inflammation with strong possibilities for therapeutic development. Ceramidase and Sphingosine Kinase (SK) are two very critical enzymes in sphingolipid metabolism as they are implicated in the regulation of bioactive sphingolipid levels. Ceramidases breakdown ceramide to generate sphingosine, which is then phosphorylated by SK to yield sphingosine-1-phosphate (S1P). S1P, a highly bioactive sphingolipid, is produced in many inflammatory cells and acts both extracellularly and intracellularly on recently defined targets. S1P mediates/modulates several important biologic activities including inflammatory responses. Recently we have begun to uncover a specific role for acid ceramidase (AC) in inflammation in cells and in mouse models of inflammation. In addition, we have chemically synthesized several AC inhibitors and begun testing them for biologic activity. Our laboratory also pioneered studies on the role of SK1 in inflammation and we have specifically demonstrated a key role for SK1/S1P in regulating the induction of the cyclooxygenase (COX-2)/prostaglandin pathway in vitro and in mouse models of colitis and arthritis. In addition we have synthesized specific SK1 inhibitors and tested them for biologic activity. Importantly, our studies are leading us to appreciate complexities in vivo whereby altering the AC/SK1/S1P pathway in immune cells versus epithelial cells may differentially regulate inflammatory responses in mice. Moreover, our data show that SK1 has cardiovascular-sparing effects when compared with COX inhibitors. These data, therefore, lead us to propose the hypothesis that the AC/SK1/S1P pathway is a fundamental pathway in inflammatory diseases and that targeting the pathway may result in novel disease-modifying therapy in inflammation. This hypothesis will be addressed by the following Specific Aims: 1. Establish and define the role of AC in mouse models of inflammation. 2. Establish and define the role of SK1 in mouse models of inflammation. 3. Develop pharmacologic inhibition of AC and SK1 as novel inflammatory therapeutic targets. These compelling studies will not only implicate the pathway of AC/SK1/S1P at the center of the inflammatory process but will also begin to reveal clear and highly relevant differences over the COX-2 pathway that could lead to ground breaking novel anti-inflammatory therapy.

描述（由申请人提供）： 该项目的长期目标是定义生物活性鞘脂代谢酶在炎症中的作用，并将这些酶靶向用于新型抗炎疗法。 PI的实验室在鞘脂代谢和功能方面具有既定的专业知识记录。从上一期资金期开始的研究使我们朝着炎症中生物活性鞘脂代谢酶的作用和调节方向迈出了一个新的激动人心的方向，具有治疗性发育的强大可能性。神经酰胺酶和鞘氨醇激酶（SK）是鞘脂代谢中的两个非常关键的酶，因为它们与生物活性鞘脂水平的调节有关。神经酰胺酶分解神经酰胺会产生鞘氨醇，然后将其用SK磷酸化，以产生1-磷酸盐（S1P）。 S1P是一种高度生物活性鞘脂，在许多炎症细胞中产生，细胞外和细胞内作用于最近定义的靶标。 S1P介导/调节几种重要的生物学活性，包括炎症反应。最近，我们开始发现细胞和小鼠炎症模型中酸性神经酶（AC）（AC）的特定作用。此外，我们已经化学合成了几种AC抑制剂，并开始对其进行生物活性测试。我们的实验室还开创了SK1在炎症中的作用的开创性研究，我们特别证明了SK1/S1P在调节体外和结肠炎和关节炎小鼠模型中的环氧合酶（COX-2）/前列腺素途径中的关键作用。此外，我们已经合成了特定的SK1抑制剂，并测试了它们的生物活性。重要的是，我们的研究使我们理解体内的复杂性，从而改变免疫细胞中的AC/SK1/S1P途径与上皮细胞可能会差异地调节小鼠的炎症反应。此外，我们的数据表明，与COX抑制剂相比，SK1具有心血管的效果。因此，这些数据使我们提出了这样的假设：AC/SK1/S1P途径是炎症性疾病的基本途径，而靶向途径可能会导致炎症中新型疾病修饰治疗。该假设将通过以下特定目的来解决：1。建立和定义AC在炎症小鼠模型中的作用。 2。建立并定义SK1在炎症小鼠模型中的作用。 3。将AC和SK1的药理抑制作用作为新型炎症治疗靶标。这些引人注目的研究不仅将暗示AC/SK1/S1P在炎症过程的中心的途径，而且还将开始揭示COX-2途径上的明显且高度相关的差异，这可能导致新型的新型抗炎治疗。 。