Circadian Role of Vitamin A in Regulation of Redox State

说明(申请人提供)：在许多发展中国家，维生素A缺乏仍然是一个严重的公共卫生问题。在阿根廷，10-20%的学龄儿童被记录为临床维生素A缺乏。最近，维生素A在成年小鼠和大鼠大脑中与较高认知功能相关的现象中的作用已被确立。另一方面，已有研究表明，维生素A缺乏会导致自由基产生增加和脂质过氧化。人们还知道，脂质过氧化和抗氧化防御系统的活动遵循每天的变化，因此，是在细胞节律调节机制的控制下。有证据表明，维生素A及其衍生物类维甲酸可能通过类维A核受体参与调节细胞时钟基因的激活。由于已知维生素A缺乏会导致氧化应激和脂质过氧化，大脑中活性氧水平的增加可能会导致日常认知能力下降，因此确定维生素A在氧化参数和抗氧化酶的昼夜表达中的作用是很重要的，特别是在海马区，因为它是大脑中与学习和记忆相关的区域。长期目标是了解环境和营养因素如何调节时钟和时钟控制基因的表达，从而调节健康个体的昼夜代谢、生理和行为活动。本应用的目的是确定维生素A缺乏对肝脏和海马区脂质过氧化和抗氧化基因的昼夜表达的影响。中心假说是，维生素A缺乏改变了脂质过氧化的昼夜模式，并通过改变类维A核受体的每日可获得性和/或细胞的氧化还原状态，影响抗氧化酶的时钟控制的基因表达。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规律，可能有助于确定维生素A在海马区氧化还原环境的昼夜调节中的作用，从而改善认知日常表现。

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.