The goal of this Phase I proposal is to perform lead optimization of a novel small molecular radioprotectant based on the Rx100 scaffold. Rx100, a metabolically stabilized analog of phospholipid growth factor lysophosphatidic acid (LPA), has shown promising results in mice, protecting the gut from radiation-induced mucositis, and preventing death when administered either before or up to six hours after exposure to ionizing radiation. Our knockout mouse studies indicate that LPA2 is the molecular target for radioprotection. Rx100 is a potent and full agonist at LPA2 GPCR; however, it is a partial agonist of the pro-apoptotic lipid-regulated transcription factor PPAR?. Based on our preliminary findings, we hypothesize that (1) synthetic optimization of Rx100 will provide selective LPA2 agonists devoid of PPAR? activity; (2) Rx100 analogs could be developed as potent radioprotective agents for ameliorating the gastrointestinal mucositis accompanied by cancer radiotherapy, leading to enhancement of the efficacy of radiotherapy and improvement of cancer survivors' quality of life; and (3) Rx100 analogs could be developed as a medical countermeasure against acute gastrointestinal syndrome and hematopoietic syndrome caused by unintended whole-body exposure to radiation in the events of nuclear accident or radiation terrorism. Studies proposed herein are designed to test the hypothesis that the activity of Rx100 analogs can be optimized, and the success of these studies would provide a strong foundation for the hypothesis that this new class of therapeutic agents can be developed for the effective protection of human life from inadvertent radiation exposure. The product(s) have marketable potential, because they could be used for the protection of populations potentially subjected to accidental, military, or therapeutic radiation exposure, workers in nuclear industry, astronauts and cancer patients. Unintended exposure to radiation via a nuclear accident, explosion of a """"""""dirty bomb,"""""""" can have devastating consequences to mankind. Radiation terrorism - a form of bioterrorism that exposes humans to damaging levels of radiation - is a real threat our nation faces everyday with no lesser risks than other modalities of microbial bioterrorism. Death from radiation treatment occurs from either gastrointestinal syndrome or hematopoietic syndrome due to the extreme sensitivity of stem cells to ionizing radiation. RxBio proposes to develop therapeutic agents based on Rx100's lead scaffold to prevent or minimize the damage due to radiation exposure and save innocent life in case of a nuclear or dirty-bomb explosion. This technology also offers applications for the attenuation of the side effects of radiation and chemotherapy of cancer. ? ? ?
