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. ? ? ?
| Li, Chunying; Krishnamurthy, Partha C; Penmatsa, Himabindu et al. (2007) Spatiotemporal coupling of cAMP transporter to CFTR chloride channel function in the gut epithelia. Cell 131:940-51 |
