Circadian Role of Vitamin A in Regulation of Redox State

描述（由申请人提供）：在许多发展中国家，维生素A缺乏症一直是一个重大的公共卫生问题。在阿根廷，10- 20%的学龄儿童被证明临床缺乏维生素A。最近，维生素a在成年小鼠和大鼠大脑中与高级认知功能相关的现象中发挥了作用。另一方面，研究表明维生素A缺乏会导致自由基和脂质过氧化的增加。我们也知道，脂质过氧化和抗氧化防御系统的活动遵循每日变化，因此，受细胞节律调节机制的控制。有证据表明，维生素A及其衍生物类维甲酸可能通过类维甲酸核受体参与细胞时钟基因激活的调节。由于已知维生素A缺乏会导致氧化应激和脂质过氧化，并且大脑中活性氧水平的增加可能会导致日常认知能力的降低，因此确定维生素A在氧化参数和抗氧化酶的昼夜节律表达中的作用非常重要，特别是在海马体中，因为它是与学习和记忆相关的大脑区域。长期目标是了解环境和营养因素如何调节生物钟和生物钟控制基因的表达，从而调节健康个体的昼夜节律代谢、生理和行为活动。本应用程序的目的是确定维生素A缺乏对肝脏和海马中脂质过氧化和抗氧化基因昼夜表达的影响。核心假设是，维生素A缺乏通过改变类视黄醇核受体的每日可用性和/或细胞氧化还原状态，改变脂质过氧化的昼夜节律模式，并影响抗氧化酶的生物钟控制基因表达。了解维生素A缺乏如何影响脂质过氧化和抗氧化防御的昼夜节律模式，可能有助于确定维生素A在海马氧化还原环境的昼夜节律调节中的作用，从而改善日常认知表现。

DESCRIPTION (provided by applicant): Vitamin A deficiency persists as a problem of significant public health concern in many developing countries. In Argentina 10-20 % of school-aged children are documented to be clinically vitamin A deficient. Recently, a role for vitamin A has been established in phenomena related to higher cognitive function in the adult mouse and rat brain. On the other hand, it has been shown that vitamin A deficiency results in an enhanced production of free radicals and lipid peroxidation. It is also known that lipoperoxidation and antioxidant defense system activities follow a daily variation and therefore, are under the control of cellular rhythm regulatory mechanisms. There is evidence that vitamin A and its derivatives, the retinoids, may contribute to the regulation of cell clock gene activation through retinoid nuclear receptors. Since vitamin A deficiency is known to lead to oxidative stress and lipoperoxidation and that increased levels of reactive oxygen species in the brain might contribute to reduced daily cognitive capacity, it would be important to define the role of vitamin A in the circadian expression of oxidative parameters and antioxidant enzymes, particularly in hippocampus, as it is the brain area related to learning and memory. The long-term goal is to understand how environmental and nutritional factors regulate the expression of clock and clock-controlled genes and thus the circadian metabolic, physiological and behavioral activities of a healthy individual. The objective of this application is to determine the impact of vitamin A deficiency on the circadian expression of lipid peroxidation and antioxidant genes in liver and hippocampus. The central hypothesis is that vitamin A deficiency modifies the circadian pattern of lipoperoxidation and affects the clock-controlled gene expression of antioxidant enzymes by modifying the daily availability of retinoid nuclear receptors and/or the cellular redox state. Understanding how vitamin A deficiency affects circadian patterns of lipoperoxidation and antioxidant defenses may contribute to establish a role for vitamin A in the circadian regulation of redox environment in the hippocampus, in order to get an improved cognitive daily performance.