Protection against radiation-induced damage to intestinal nutrient transport

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DESCRIPTION (provided by applicant): A major focus area of RFA-AI-07-013 is the development of medical products that can protect and restore nutrient transport in the event of gastrointestinal irradiation during an accidental radiological event or intentional attack. The radiation exposures may be delivered acutely or chronically, by external or internal sources, and by low- and high-linear energy transfer (LET) radiations. This may involve large numbers of victims that exceed our capacity to triage and treat, and argue for the development of non-toxic medical products that are readily available to the public. There is considerable evidence to suggest that naturally occurring antioxidant vitamins may provide a long window of protection against effects caused by these exposure conditions. Antioxidant vitamins substantially reduce radiation-induced damage caused by acute and chronic exposures to low-LET radiations and chronic exposures to high-LET radiations. Vitamin mixtures have reduced intestinal side effects caused by radiation. Therefore, antioxidant vitamins may be efficacious in protecting and restoring intestinal nutrient transport during radiological emergencies. For almost all nutrients, the rate-limiting step of intestinal absorption is transport across the apical membrane. Our preliminary work manifests damage to this transport at sublethal radiation doses below those that perturb other intestinal functions. Our long term goal is to identify non-toxic radioprotectors capable of preventing, mitigating, and treating the deleterious effect of ionizing radiations on nutrient transport, and to understand the effects of ionizing radiations on intestinal nutrient absorption. The specific aims are 1) to establish the effects of ionizing radiation on absorption of metabolically important nutrients as well as on the mRNA and protein expression of nutrient transporters, for later use in quantifying DMFs; 2) because radiation perturbs oxidative metabolism, to examine whether energy-dependent nutrient transport processes are more radiosensitive than facilitative nutrient transport processes that do not require an energy source; 3) to determine whether radiation alters intestinal membrane permeability; and 4) to quantify by DMFs the effectiveness of antioxidant vitamins A, C, and E, administered individually or in concert, to protect and mitigate against the deleterious effects of ionizing radiations on nutrient transport. Three sources of radiation will be used in each aim: acute 137Cs gamma rays, chronic 137Cs gamma rays, and alpha particles from 210Po. We have found that vitamins mitigate biological effects of low- and high-LET radiation in testes. Since spermatogenic and intestinal crypt cycles share many similarities, we anticipate that vitamins A, C and E will also reduce radiation-induced damage to the intestinal mucosa and nutrient transport. Finally, this project will also delineate the differential radiosensitivity of different classes of nutrient transport processes, and their differential radioprotection by antioxidant vitamins.