Bioactive Sphingolipid enzymes as targets in inflammation

描述（由申请人提供）： 该项目的长期目标是确定生物活性鞘脂代谢酶在炎症中的作用，并靶向这些酶用于新型抗炎治疗。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。上一个资助期的研究使我们进入了一个新的令人兴奋的方向，即生物活性鞘脂代谢酶在炎症中的作用和调节，具有很强的治疗开发可能性。神经酰胺酶和鞘氨醇激酶（SK）是鞘脂代谢中的两种非常关键的酶，因为它们涉及生物活性鞘脂水平的调节。神经酰胺酶分解神经酰胺以产生鞘氨醇，然后鞘氨醇被SK磷酸化以产生鞘氨醇-1-磷酸（S1 P）。S1 P是一种高度生物活性的鞘脂，在许多炎症细胞中产生，并在细胞外和细胞内作用于最近定义的靶点。S1 P介导/调节几种重要的生物活性，包括炎症反应。最近，我们已经开始发现酸性神经酰胺酶（AC）在细胞炎症和小鼠炎症模型中的特定作用。此外，我们已经化学合成了几种AC抑制剂，并开始测试它们的生物活性。我们的实验室还率先研究了SK 1在炎症中的作用，并且我们特别证明了SK 1/S1 P在体外和小鼠模型中调节环氧合酶（考克斯-2）/前列腺素途径诱导方面的关键作用。结肠炎和关节炎。此外，我们还合成了特异性SK 1抑制剂，并测试了它们的生物活性。重要的是，我们的研究使我们认识到体内的复杂性，从而改变免疫细胞与上皮细胞中的AC/SK 1/S1 P通路可能会差异调节小鼠的炎症反应。此外，我们的数据表明，SK 1具有心血管保护作用相比，考克斯抑制剂。因此，这些数据使我们提出这样的假设，即AC/SK 1/S1 P通路是炎症性疾病的基本通路，靶向该通路可能导致炎症中新的疾病修饰疗法。这一假设将通过以下具体目标来解决：1。建立并确定AC在小鼠炎症模型中的作用。2.建立并确定SK 1在小鼠炎症模型中的作用。3.开发AC和SK 1的药理学抑制作用，作为新的炎症治疗靶点。这些令人信服的研究不仅将涉及AC/SK 1/S1 P途径在炎症过程的中心，但也将开始揭示明确和高度相关的差异，考克斯-2途径，可能导致开创性的新的抗炎治疗。

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.