THERAPEUTIC APPROACH TO SULFUR MUSTARD EXPOSURE

硫芥菜暴露的治疗方法

• 批准号: 6739318
• 负责人: Roger A Sabbadini
• 金额: $ 39.97万
• 依托单位: LPATH THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6739318
• 关键词: biological signal transduction; bioterrorism /chemical warfare; drug design /synthesis /production; drug discovery /isolation; environmental exposure; enzyme linked immunosorbent assay; gas poisoning; genetically modified animals; hybridomas; immune response; immunologic substance development /preparation; inflammation; interleukin 6; interleukin 8; keratinocyte; laboratory mouse; monoclonal antibody; mustard compounds; respiratory disorder chemotherapy; skin disorder chemotherapy; sphingomyelin phosphodiesterase; sphingosine; tissue /cell culture; tumor necrosis factor alpha

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

描述（由申请人提供）：最近的许多工作都指出炎症在硫芥（SM）毒性中起着至关重要的作用，并且已经观察到标准抗炎剂（例如地塞米松）在治疗 SM 损伤方面具有一定功效。最近的研究结果深刻表明鞘脂是许多炎症和免疫调节过程中的关键因子，但迄今为止，这一新兴认识尚未应用于 SM 损伤的治疗或诊断/预后。这种脂质信号炎症级联反应中的两个重要治疗靶点是 L-磷酸鞘氨醇 (S 1P) 和中性鞘磷脂酶 (nSMase)。拟议研究的总体目标是将 Medlyte 在这些脂质信号剂方面发现和开发的成果应用于治疗和诊断 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 S 1P）的产生介导接触 SM 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皮肤暴露小鼠耳起泡模型，使用我们内部的敲除小鼠模型，该模型缺乏鞘脂信号系统的关键成分。我们预计 KO 小鼠对 SM 暴露具有更强的抵抗力。预计 S1P 将成为炎症反应中的主要脂质介质，除了我们计划的旨在通过阻断 nSMase 来限制鞘脂产生的 II 期小分子药物开发计划外，我们还将开发针对 S1P 的单克隆抗体作为潜在的治疗方法。 鞘脂作为 SM 毒性介质的含义应该为开发更有效的治疗方法提供机会，特别是更严重的肺部暴露。第一阶段的预期成功将使我们能够开展第二阶段研究计划，为暴露于 SM 的患者开发一种基于鞘脂的治疗方法