ZN DEFICIENCY IMPAIRS BBB INTEGRITY FR OXIDATIVE STRESS

缺锌会损害血脑屏障完整性和氧化应激

• 批准号: 6363932
• 负责人: TAMMY M BRAY
• 金额: $ 19.71万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-15 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6363932
• 关键词: blood brain barrier; brain metabolism; diet therapy; dietary trace element; disease /disorder prevention /control; free radicals; hyperoxia; laboratory rat; magnetic resonance imaging; membrane permeability; nervous system disorder; nuclear magnetic resonance spectroscopy; nutrition disorders; nutrition related tag; oxidative stress; zinc

DESCRIPTION: (Verbatim from the Applicant's Abstract) The importance of Zn in brain function and neurobiology is widely acknowledged, and many human neurological diseases have been linked to Zn deficiency. However, the mechanism by which dietary Zn deficiency may lead to pathology in the brain, an organ highly susceptible to oxidative damage, is not yet clear. Investigations into the effect of oxidative stress on brain function are often complicated by the high propensity of brain tissue to develop artifactual indices of oxidative stress in vivo. We will pioneer the application of non-invasive in vivo MRI and 31P-NMR techniques to study the role of Zn nutrition in maintaining the integrity of the blood brain barrier(BBB) and brain energy metabolism under oxidative stress. Further, we will identify possible cellular and molecular mechanisms for Zn deficiency pathology under oxidative stress. Hence the focus of this proposal is to examine the role of Zn nutrition in coping with oxidative stress to prevent brain disorders. The long term goal of this research is to understand the basic mechanism underlying the relationship between dietary Zn and optimal central nervous system(CNS) function. We speculate that sub-optimal Zn nutrition weakens BBB integrity and that oxidative stress superimposed upon Zn deficiency disrupts the protective function of the BBB, an event that may be pivotal in the pathogenesis of many brain disorders. Consequently, perturbations of cerebral homeostasis following loss of BBB integrity may lead to impaired energy metabolism and increased oxidative stress within the brain, a sequence of metabolic and biochemical changes by which Zn deficiency may contribute to the development of brain disorders. Thus, the hypothesis of this project is that Zn protects the BBB against oxidative stress through its antioxidant and membrane stabilization properties and therefore helps to maintain the homeostasis of brain metabolism and prevent brain disorders. To test this hypothesis, we will quantify changes in BBB permeability and brain energy metabolism, assess the balance between free radical defense and free radical generation, and measure the extent of oxidative damage in the brain of Zn deficient rats during exposure to hyperoxia. In addition, the possible underlying mechanisms will be explored. This research will contribute significantly to our understanding of the mechanistic roles of Zn in the etiology of brain disorders and lead to the development of better strategies for disease prevention.

描述：（逐字摘自申请人摘要）锌在 脑功能和神经生物学已被广泛认可，许多人类 神经系统疾病与锌缺乏有关。然而，该机制 饮食中的锌缺乏可能会导致大脑（一个器官）出现病变 高度易受氧化损伤，目前尚不清楚。调查 氧化应激对大脑功能的影响常常因以下因素而变得复杂 脑组织高度倾向于产生人为的氧化指数 体内的压力。我们将开创无创体内 MRI 的应用 31P-NMR 技术研究锌营养在维持 血脑屏障（BBB）的完整性和脑能量代谢 氧化应激。此外，我们将确定可能的细胞和分子 氧化应激下锌缺乏病理机制。因此重点 该提案的目的是研究锌营养在应对 氧化应激可预防大脑疾病。本次活动的长远目标 研究是为了了解这种关系背后的基本机制 膳食锌与最佳中枢神经系统 (CNS) 功能之间的关系。我们 推测次优的锌营养会削弱血脑屏障的完整性 锌缺乏叠加氧化应激会破坏保护作用 BBB 的功能，这一事件可能在许多疾病的发病机制中至关重要 脑部疾病。因此，大脑稳态的扰动 血脑屏障完整性的丧失可能会导致能量代谢受损并增加 大脑内的氧化应激，一系列代谢和生化反应 锌缺乏可能导致大脑发育发生变化 失调。因此，该项目的假设是 Zn 保护 BBB 通过其抗氧化和膜稳定性来对抗氧化应激 特性，因此有助于维持大脑新陈代谢的稳态 并预防脑部疾病。为了检验这个假设，我们将量化变化 血脑屏障通透性和脑能量代谢，评估两者之间的平衡 自由基防御和自由基产生，并测量自由基的程度 缺锌大鼠的大脑在暴露于 高氧。此外，还将探讨可能的潜在机制。 这项研究将极大地促进我们对 锌在脑部疾病病因学中的机制作用并导致 制定更好的疾病预防策略。