Vibrio Cholerae as a bioterror agent: New means of treating a potential pandemic

描述（由申请人提供）：霍乱是一种严重的肠道疾病，由霍乱弧菌（一种革兰氏阴性细菌）引起，有可能通过污染水和食品供应而被用作生物恐怖武器。美国国家过敏和传染病研究所（NIAID）已将霍乱弧菌归类为“B”类病原体，这是一种潜在的生物恐怖主义威胁。溶血磷脂酸（LPA）是存在于血液和食物中的脂质介质。LPA已被证明是一种LPA受体激动剂，有利于减少炎症性肠病和腹泻的体重减轻。我们将提供初步的数据，以显示在小鼠中由胆固醇毒素（CTX）诱导的肠液分泌显着减少LPA管理。基于这一观察结果，拟议的研究将测试富含LPA和稳定的合成LPA受体激动剂的食物可以抑制CTX诱导的小鼠分泌性腹泻的假设。因此，除了口服补液疗法之外，使用脂质介质如LPA及其类似物将在治疗霍乱弧菌大流行中具有价值。 这项建议的具体目标是： 目的1：研究富含LPA的食物对环磷酰胺所致小鼠腹泻的抑制作用。 目的2：测试代谢稳定的合成LPA受体激动剂是否表现出有效的抗真菌特性（与LPA相比）。 这些研究将证明，霍乱毒素引起的腹泻可以通过食用富含LPA的食物来控制。它还将帮助我们测试和开发可能具有治疗潜力的药物。这将有助于我们朝着理解脂质介质的长期目标前进，LPA）对CFTR Cl-通道功能有调节作用。这些研究的结果将为我们提供治疗胃肠道疾病（如分泌性腹泻）的可能替代方法，这些疾病可能是由于生物恐怖行为（如用霍乱弧菌污染食物和水源）或自然原因引起的。

DESCRIPTION (provided by applicant): Cholera is a serious diarrheal disease and is caused by Vibrio cholerae a gram negative bacterium and has the potential to be used as a bioterror weapon by contaminating water and food supplies. The National Institute of Allergy and Infectious Diseases (NIAID) has categorized V. cholerae as category "B" pathogen that posses a potential bioterrorism threat. Lysophosphatidic acid (LPA) is a lipid mediator present in blood and foods. LPA has been shown to be an LPA-receptor agonist and is beneficial in reducing weight loss in inflammatory bowel disease and diarrhea. We will provide preliminary data to show that intestinal fluid secretion induced by cholerae toxin (CTX) in mice is significantly reduced by LPA administration. Based on this observation, the proposed research will test the hypothesis that foods rich in LPA and stabilized synthetic LPA-receptor agonists can inhibit CTX-induced secretory diarrhea in mice. Therefore the use of lipid mediators such as LPA and its anologs in addition to oral rehydration therapy would have value in treating V. cholerae pandemic. The specific aims of this proposal are: Aim 1: To test if foods rich in LPA will inhibit CTX-induced diarrhea in mice. Aim 2: To test if metabolically stabilized synthetic LPA-receptor agonists exhibit potent anti- diarrheal properties (compared to LPA). These studies will demonstrate that cholera toxin-induced diarrhea can be controlled by consuming foods rich in LPA. It will also help us test and develop drugs that may have therapeutic potential. It will help move us toward the long-term goal of understanding the lipid mediators which (e.g., LPA) can regulate the CFTR Cl- channel function. The results of these studies will provide us with possible alternative methods of treating diseases of the gastrointestinal tract such as secretory diarrhea, that can be caused due to an act of bioterror such as contaminating food and water supplies with V. cholerae or due to natural causes.