The anti-diarrheal potential of a LPA analog Rx100

DESCRIPTION provided by applicant Secretory diarrhea is a leading cause of death worldwide among children under the age of five Its pathology involves cystic fibrosis transmembrane conductance regulator CFTR which provides a primary pathway for Cl secretion Targeting CFTR to prevent reduce losses of electrolytes and water is a therapeutic strategy Lysophosphatidic acid LPA a naturally occurring phospholipid mediator acts through G protein coupled receptors GPCRs Our research group has demonstrated that the LPA GPCR inhibits CFTR dependent Cl transport in intestinal epithelial cells We have synthesized Rx a potent and metabolically stabilized agonist for the LPA GPCR We have demonstrated that Rx significantly inhibited cholera toxin CTX induced CFTR mediated secretory diarrhea in mice We propose to develop Rx into a highly effective anti diarrheal agent Aim Optimize the efficacy of Rx in inhibiting CTX induced diarrhea Determine the oral bioavailability of Rx in mice Determine and optimize the anti diarrheal effect of Rx by oral delivery Determine and optimize the anti diarrheal effect of Rx by parenteral delivery Aim Confirm the efficacy of Rx in inhibiting CTX induced diarrhea Aim Evaluate the anti diarrheal effect of Rx in inhibiting Escherichia coli toxin and Citrobacter rodentium infection induced diarrhea in mice Methods Oral Rx bioavailability under will be determined using tandem mass spectrometry detection LC MS MS For Rx andapos s efficacy studies under andamp we will use an open loop mouse model of CTX induced diarrhea We will confirm Rx andapos s efficacy under aim using a closed loop mouse model of CTX induced diarrhea We will also test Rx andapos s efficacy in a closed loop model of Escherichia coli heat stable toxin induced intestinal fluid secretion under aim We will also test Rx andapos s efficacy using a mouse model of C rodentium infection under aim Relevance to Public Health Rx can be developed into a highly effective anti diarrheal drug for the benefit of human beings PUBLIC HEALTH RELEVANCE Secretory diarrhea is a leading cause of death worldwide among children under the age of five No truly satisfactory therapeutic agents are available yet and oral rehydration remains the primary approach in managing secretory diarrhea We propose to develop Rx into a highly effective anti diarrheal agent