THERAPEUTIC APPROACH TO SULFUR MUSTARD EXPOSURE

描述(申请人提供)：许多最近的工作指出炎症在硫磺芥末(SM)毒性中起着至关重要的作用，并且已经观察到地塞米松等标准抗炎剂在治疗SM损伤方面的一些疗效。最近的发现深刻地表明鞘磷脂是许多炎症和免疫调节过程中的关键因素，但到目前为止，这种新的认识还没有被应用于SM损伤的治疗或诊断/预后。在这一脂质信号炎症级联反应中，两个重要的治疗靶点是神经鞘氨醇-L-磷酸(S 1P)和中性神经鞘磷脂酶(NSMase)。这项拟议研究的总体目标是将Medlyte在这些脂质信号制剂方面发现和开发的东西应用于治疗和诊断SM损伤的产品的发现和开发。在这方面，与S1P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磷脂在SM毒性引发的炎症过程中的作用。具体地说，我们将证明鞘磷脂(主要是S 1P)的产生介导了SM暴露后的炎症反应。我们将首先采用角质形成细胞培养模型来确定鞘磷脂炎症介质是否参与细胞对SM的反应。我们还打算采用成熟的小鼠耳发泡剂皮肤暴露模型，使用我们的内部基因敲除小鼠模型，该模型缺乏鞘磷脂信号系统的关键成分。我们预计KO小鼠将对SM暴露有更强的抵抗力。预计S1P将成为炎症反应中的主要脂质介质，除了我们计划的第二阶段小分子药物开发计划外，我们还将开发针对S 1P的单抗作为潜在的治疗药物，旨在通过阻断nSMase来限制鞘磷脂的产生。 鞘磷脂作为SM毒性的介体，应该为开发更有效的治疗方法，特别是更严重的肺部暴露提供机会。第一阶段的预期成功将使我们进入第二阶段的研究计划，为接触SM的患者开发一种基于鞘磷脂的治疗方法

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