Protection against radiation-induced damage to intestinal nutrient transport

防止辐射引起的肠道营养运输损伤

• 批准号: 7472929
• 负责人: Roger W. Howell
• 金额: $ 87.07万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7472929
• 关键词: Acute; Adverse effects; Alpha Particles; Alpha Rays; Antioxidants; Area; Biological; Cell Membrane Permeability; Cell Respiration; Chronic; Class; Condition; Development; Dose; Effectiveness; Emergency Situation; Energy-Generating Resources; Event; Exposure to; Gamma Rays; Goals; High-LET Radiation; Intestinal Absorption; Intestinal Mucosa; Intestines; Ionizing radiation; Medical; Messenger RNA; Numbers; Nutrient; Radiation; Radiation Tolerance; Radiation induced damage; Radioprotection; Rate; Source; Testis; Transport Process; Triage; Vitamin A; Vitamins; Work; absorption; apical membrane; gastrointestinal; intestinal crypt; irradiation; prevent; protein expression

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.

描述（由申请方提供）：RFA-AI-07-013的一个主要关注领域是开发在意外放射事件或故意攻击期间发生胃肠道辐照时能够保护和恢复营养转运的医疗产品。 辐射暴露可以通过外部或内部源以及低线性和高线性能量转移（LET）辐射进行急性或慢性传递。 这可能涉及大量的受害者，超出了我们的分类和治疗能力，并主张开发公众可以随时获得的无毒医疗产品。 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长时间的保护窗口，防止这些暴露条件引起的影响。 抗氧化维生素可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，抗氧化维生素可能是有效的保护和恢复肠道营养物质的运输在放射性紧急情况。 对于几乎所有的营养素，肠道吸收的限速步骤是通过顶膜转运。 我们的初步工作表明，在低于那些扰乱其他肠道功能的亚致死辐射剂量下，这种运输受到损害。 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转运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吸收的影响。 具体目标是：1）确定电离辐射对代谢重要营养素吸收以及营养素转运蛋白mRNA和蛋白质表达的影响，以便以后用于量化DMF; 2）由于辐射干扰氧化代谢，因此检查依赖能量的营养素转运过程是否比不需要能量源的促进性营养素转运过程更敏感; 3）确定辐射是否改变肠膜渗透性;和4）通过DMF量化抗氧化剂维生素A、C和E单独或共同施用的有效性，以保护和减轻电离辐射对营养物运输的有害影响。每个目标将使用三种辐射源：急性137 Cs伽马射线，慢性137 Cs伽马射线和210 Po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也将减少辐射引起的肠粘膜损伤和营养转运。 最后，本项目还将描述不同类别的营养物质运输过程的差异辐射敏感性，以及抗氧化维生素的差异辐射防护。