Metabolic and Immune Functions of Zinc

我的研究项目一直在研究锌在细胞防御和代谢中的作用。细胞防御机制的研究主要集中在缺锌和补锌对机体免疫功能和抗氧化保护的影响。我们是第一个表明缺锌大鼠T细胞中一种名为“Lck”的蛋白质升高的小组。这是一个重要的发现，因为Lck参与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，我们是第一组表明缺锌大鼠在血液中循环或脾脏中存在较少的新释放的T细胞。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细胞对广泛的外源抗原作出反应的多样性。我们提出，这些新释放的T细胞在锌缺乏的动物可能更容易受到一种类型的细胞死亡称为凋亡，然而，这是不是这样的。事实上，我们的一些数据表明锌缺乏时存在抗凋亡反应。因此，我们对锌和免疫功能的研究挑战了文献中关于锌，细胞凋亡和细胞信号传导的公认观点。我们希望了解更多关于锌状态，Lck，T细胞信号传导，凋亡和新释放的T细胞对免疫挑战的反应之间的关系。我们一直在研究一种称为金属硫蛋白或'MT'的蛋白质在细胞防御中的作用。MT保护细胞免受应激。MT以及锌转运蛋白控制细胞内锌的量和形式。我们提出，由于缺锌导致的T细胞内游离锌的变化有助于改变T细胞信号传导，降低缺锌时的免疫功能。因此，我们计划研究缺锌和补锌对T细胞内游离锌、MT、细胞应激、细胞凋亡和信号转导的影响。生长期动物缺锌引起的免疫功能下降与其采食量减少、生长和代谢有关。锌领域长期存在的挑战之一是确定缺锌饮食如何以及为什么会大大减少啮齿动物的摄食量。如果一只缺锌的老鼠被喂食含锌的食物，它的摄食量会在几小时内增加。如果换回缺锌饮食，它的摄食量在几小时内再次下降。缺锌动物的摄食量减少对它们的生存至关重要，因为强行喂食缺锌饮食会导致死亡。没有其他营养素具有这种效果。锌在这种快速响应控制采食量和协调控制代谢途径中的关键目标尚未确定。我们希望确定血浆锌的波动如何改变血浆代谢产物谱并影响采食量和代谢，以及从长远来看，这种反应如何与缺锌时免疫反应降低有关。这项研究计划具有很高的影响力，因为它挑战了目前公认的锌，细胞凋亡和免疫功能障碍的信念。这是新的，因为没有其他小组正在研究锌，LCK，最近的胸腺移民，细胞凋亡和免疫功能之间的关系。我们的研究计划已经并将继续有助于营养免疫学和代谢的基础科学的理解，在锌的背景下，代谢和免疫功能的关键营养素。该发现计划将显著影响我们对锌在细胞和全身防御中的分子作用的理解，包括细胞内游离锌在免疫功能的细胞信号传导中以及血浆锌在协调代谢反应中的作用。

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.