THERAPEUTIC APPROACH TO SULFUR MUSTARD EXPOSURE

描述（由申请人提供）：最近的许多工作表明炎症在硫芥（SM）毒性中起着至关重要的作用，并且已经观察到使用标准抗炎剂（如地塞米松）治疗SM损伤的一些疗效。最近的研究结果深刻地暗示了鞘脂作为许多炎症和免疫调节过程中的关键试剂，但这种新兴的理解，迄今为止，尚未应用于SM损伤的治疗或诊断/预后。这种脂质信号传导炎症级联中的两个重要治疗靶标是鞘氨醇-1-磷酸（S1 P）和中性鞘磷脂酶（nSMase）。拟议研究的总体目标是将Medlyte在这些脂质信号传导剂方面发现和开发的内容应用于发现和开发治疗和诊断SM损伤的产品。在这方面，与S1 P和中性鞘磷脂酶相关的发现和方法是Medlyte技术的核心。我们打算表征并最终证明鞘脂在SM毒性引发的炎症过程中的作用。具体来说，我们将证明鞘脂（主要是S1 P）的产生介导了暴露于SM后的炎症反应。我们将首先采用角质形成细胞培养模型，以确定鞘脂炎症介质是否参与细胞对SM的反应。我们还打算使用我们的内部敲除小鼠模型（缺乏鞘脂信号传导系统的关键组分），采用成熟的皮肤暴露小鼠耳部起泡模型。我们预期KO小鼠将对SM暴露更具抗性。预期S1 P将是炎症反应中的主要脂质介质，我们将开发针对S1 P的单克隆抗体作为潜在的治疗剂，除了我们计划的II期小分子药物开发计划，旨在通过阻断nSM酶限制鞘脂的产生。 鞘脂作为SM毒性介质的意义应该提供一个机会，以开发更有效的治疗方法，特别是更严重的肺部暴露。I期的预期成功将使我们能够进行II期研究计划，为暴露于SM的患者开发基于鞘脂的治疗药物

DESCRIPTION (provided by applicant): Much recent work points to inflammation as playing a vital role in sulfur mustard (SM) toxicity, and some efficacy in the treatment of SM injury has been observed with standard anti-inflammatory agents such as dexamethasone. Recent findings have profoundly implicated sphingolipids as critical agents in many inflammatory and immuno-modulatory processes, but this emerging understanding has, to date, not been applied to the treatment or diagnosis/prognosis of SM injury. Two important therapeutic targets in this lipid signaling inflammatory cascade are sphingosine-l-phosphate (S 1P) and neutral sphingomyelinase (nSMase). The over-all goal of the proposed research is to apply what has been discovered and developed at Medlyte with respect to these lipid-signaling agents to the discovery and development of products to treat and diagnose SM injury. In this regard, findings and methods associated with S1P and neutral sphingomyelinase are the core of the Medlyte technology. We intend to characterize and conclusively demonstrate the role of sphingolipids in the inflammatory process initiated by SM toxicity. Specifically, we will demonstrate that production of sphingolipids (primarily S 1P) mediates the inflammatory response that follows exposure to SM. We will initially employ a keratinocyte cell culture model to determine if the sphingolipid inflammatory mediators are participatory in cell's response to SM. We also intend to employ the well-established mouse ear vesicant model of cutaneous exposure using our in-house knockout mouse model that lacks key components of the sphingolipid signaling system. We anticipate that the KO mice will be more resistant to SM exposure. Anticipating the S1P will be the major lipid mediator in the inflammatory response, we will develop monoclonal antibodies against S 1P as a potential therapeutic in addition to our planned Phase II small molecule drug development program designed to limit sphingolipid production through blocking nSMase. Implication of sphingolipids as mediators of SM toxicity should provide an opportunity to develop more effective therapeutics, particularly the more serious pulmonary exposures. The anticipated success of Phase I will position us for a Phase II research plan to develop a sphingolipid-based therapeutic for patients exposed to SM