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在意外放射事件或故意攻击期间发生胃肠道照射时可以保护和恢复营养物质运输的医疗产品。辐射暴露可以是急性或慢性的，可以是外部或内部的，可以是低线性和高线性能量转移（LET）辐射。这可能涉及大量超出我们分诊和治疗能力的受害者，并主张开发对公众随时可用的无毒医疗产品。有相当多的证据表明，天然存在的抗氧化维生素可以提供一个较长的保护期，防止这些暴露条件造成的影响。抗氧化维生素大大减少急性和慢性暴露于低let辐射和慢性暴露于高let辐射所造成的辐射引起的损伤。维生素混合物减少了辐射引起的肠道副作用。因此，抗氧化维生素可能有效地保护和恢复放射性紧急情况下肠道营养物质的运输。对于几乎所有的营养物质，肠道吸收的限速步骤是通过根尖膜的运输。我们的初步工作表明，低于扰乱其他肠道功能的亚致死辐射剂量对这种运输造成损害。我们的长期目标是确定能够预防、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保护剂，并了解电离辐射对肠道营养物质吸收的影响。具体目的是：1)确定电离辐射对代谢重要营养素吸收的影响，以及对营养转运体mRNA和蛋白质表达的影响，以便以后用于定量DMFs；2)由于辐射干扰氧化代谢，研究能量依赖性营养转运过程是否比不需要能量源的促进性营养转运过程对辐射更敏感；3)测定辐射是否改变肠膜通透性；4)通过DMFs量化抗氧化维生素A、C和E单独或协同使用的有效性，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伽马射线和来自210Po的α粒子。我们发现维生素可以减轻睾丸中低let和高let辐射的生物学效应。由于生精周期和肠隐窝周期有许多相似之处，我们预计维生素A、C和E也会减少辐射引起的肠黏膜损伤和营养物质运输。最后，本项目还将描述不同种类的营养物质运输过程的不同辐射敏感性，以及抗氧化维生素对它们的不同辐射防护。

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.