Metabolic and Immune Functions of Zinc

点击翻译按钮获取中文摘要

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.