Metabolic and Immune Functions of Zinc

锌的代谢和免疫功能

• 批准号: RGPIN-2014-05973
• 负责人: Taylor, Carla
• 金额: $ 2.48万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=611950
• 关键词: Metabolic; Immune; Functions; Zinc

My research program has been investigating the role of zinc in cellular defense and metabolism. The cellular defense research has focused on the studying the effects of dietary zinc deficiency and zinc supplementation on immune function and antioxidant protection. We are the first group to show that a protein called ‘Lck’ is elevated in T cells of zinc-deficient rats. This is a significant finding because Lck is involved in the development of T cells as well as their susceptibility to cell death. T cells mature in the thymus and we are the first group to show that zinc-deficient rats have fewer newly released T cells circulating in the blood or present in the spleen. This is an important finding because a reduction in the newly released T cells will limit the diversity of T cells for responding to a wide range of foreign antigens. We proposed that these newly released T cells in Zn-deficient animals might be more susceptible to a type of cell death called apoptosis, however, this was not the case. In fact, some of our data indicates an anti-apoptotic response in zinc deficiency. Thus, our research on zinc and immune function is challenging accepted ideas in the literature about zinc, apoptosis and cell signaling. We want to learn more about the relationships among zinc status, Lck, T cell signaling, apoptosis and the response of the newly released T cells to an immune challenge. We have been investigating the roles of a protein called metallothionein or ‘MT’ in cellular defense. MT protects against cellular stress. MT as well as zinc transporter proteins control the amount and form of zinc inside cells. We are proposing that changes in intracellular free zinc in T cells due to zinc deficiency contribute to altered T cell signaling and reduced immune function in zinc deficiency. Thus, we plan to investigate the effects of zinc deficiency and supplementation on intracellular free zinc, MT, cellular stress, apoptosis and signaling in T cells. The reduced immune function due to zinc deficiency in growing animals is related to their reduced feed intake, growth and metabolism. One of the longstanding challenges in the zinc field has been determining how and why a zinc deficient diet greatly reduces feed intake in rodents. If a zinc-deficient rat is fed a diet containing zinc, its feed intake will increase within hours. If switched back to a zinc deficient diet, its feed intake drops again within hours. The reduced feed intake by zinc-deficient animals is critical for their survival as force-feeding a zinc-deficient diet will cause death. No other nutrient has this effect. The key targets of zinc in this rapidly responding control of feed intake and the coordinated control of metabolic pathways have not been defined. We want to determine how fluctuations in plasma zinc change the plasma metabolite profile and affect feed intake and metabolism, and in the longer term, how this response is related to the reduced immune response in zinc deficiency. This research program has high impact as it is challenging currently accepted beliefs about zinc, apoptosis and immune dysfunction. It is novel as no other group is working on the relationships among zinc, Lck, recent thymic emigrants, apoptosis and immune function. Our research program has and will continue to contribute to the basic sciences understanding of nutritional immunology and metabolism in the context of zinc, a critical nutrient for metabolic and immune function. This Discovery Program will significantly impact on our understanding of the molecular role of Zn in cellular and whole-body defense, including intracellular free Zn in cell signaling for immune function and plasma Zn in coordinating metabolic responses.

我的研究项目一直在研究锌在细胞防御和代谢中的作用。细胞防御研究的重点是研究膳食缺锌和补锌对免疫功能和抗氧化保护的影响。我们是第一个发现一种叫做“Lck”的蛋白质在缺锌大鼠的T细胞中升高的研究小组。这是一个重要的发现，因为Lck参与了T细胞的发育以及它们对细胞死亡的易感性。T细胞在胸腺中成熟，我们是第一个证明缺锌的大鼠血液循环中或脾脏中新释放的T细胞较少的研究小组。这是一个重要的发现，因为新释放的T细胞的减少将限制T细胞对广泛的外来抗原作出反应的多样性。我们提出，这些新释放的T细胞在缺锌动物中可能更容易受到一种称为细胞凋亡的细胞死亡的影响，然而，事实并非如此。事实上，我们的一些数据表明锌缺乏有抗凋亡反应。因此，我们对锌和免疫功能的研究正在挑战文献中关于锌、细胞凋亡和细胞信号传导的公认观点。我们想了解更多关于锌状态、Lck、T细胞信号、凋亡和新释放的T细胞对免疫挑战的反应之间的关系。