Protection against radiation-induced damage to intestinal nutrient transport

描述（由申请人提供）：RFA-AI-07-013 的一个主要重点领域是开发医疗产品，这些产品可以在意外放射事件或故意攻击期间受到胃肠道照射时保护和恢复营养物质运输。 辐射暴露可以通过外部或内部源以及通过低和高线性能量转移（LET）辐射来急性或慢性地传递。 这可能涉及大量超出我们分类和治疗能力的受害者，并主张开发可供公众随时使用的无毒医疗产品。 有大量证据表明，天然存在的抗氧化维生素可以提供长时间的保护，防止这些暴露条件造成的影响。 抗氧化维生素可显着减少因急性和慢性暴露于低 LET 辐射以及长期暴露于高 LET 辐射而引起的辐射损伤。 维生素混合物可以减少辐射引起的肠道副作用。 因此，抗氧化维生素可能在放射紧急情况下有效保护和恢复肠道营养物质运输。 对于几乎所有的营养物质，肠道吸收的限速步骤是穿过顶膜的运输。 我们的初步工作表明，在低于干扰其他肠道功能的亚致死辐射剂量下，这种运输会受到损害。 我们的长期目标是找到能够预防、减轻和治疗电离辐射对营养物质运输的有害影响的无毒辐射防护剂，并了解电离辐射对肠道营养物质吸收的影响。 具体目标是 1) 确定电离辐射对代谢重要营养物质吸收以及营养转运蛋白 mRNA 和蛋白质表达的影响，以供以后用于量化 DMF； 2）由于辐射会扰乱氧化代谢，因此要检查能量依赖型营养物运输过程是否比不需要能源的促进性营养物运输过程对辐射更敏感； 3) 确定辐射是否改变肠膜通透性； 4) 通过 DMF 量化抗氧化维生素 A、C 和 E 的有效性（单独或联合施用）以保护和减轻电离辐射对营养物质运输的有害影响。每个目标将使用三种辐射源：急性 137Cs 伽马射线、慢性 137Cs 伽马射线和 210Po 的 α 粒子。 我们发现维生素可以减轻睾丸中低和高 LET 辐射的生物效应。 由于生精循环和肠隐窝循环有许多相似之处，我们预计维生素 A、C 和 E 也将减少辐射引起的对肠粘膜和营养运输的损伤。 最后，该项目还将描述不同类别的营养物运输过程的不同放射敏感性，以及抗氧化维生素对它们的不同放射防护作用。

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.