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Zinc: Future Directions


Zinc and Health: Workshop Summary

Future Directions

This NIH Workshop on Zinc and Health has served to synthesize remarkable recent progress and our understanding of zinc in health and disease.  It is abundantly clear that zinc is of extraordinary and diverse importance in human biology and nutrition.  Despite encouraging recent progress, zinc research is still in a relatively early stage of its evolution.  This workshop, however, has achieved a broad consensus on priority research areas that will be most productive in accelerating progress relevant to human health and disease.

In broad terms, these are:

I.  Accelerated research directed to achieving a clearer understanding of the chemistry, biology and pathobiology of zinc.  Specific systems meriting special focus include the gastrointestinal, immune and central nervous systems.

Research questions and directives to characterize the biological role of zinc:

  • How shall the characterization, chemistry, and thermodynamics of transporters for zinc be evaluated?
  • How are the activities of zinc finger proteins (of all classes) affected by cellular zinc status?
  • Do zinc finger proteins form zinc-regulated gene control networks?
  • Determine the relationship of zinc to the structural and biochemical properties of calcium channels.
  • Determine the neurobehavioral roles of the neuronal circuits that use synaptically-released zinc as a trans-synaptic signal
  • Characterize the time course of zinc-induced neuronal injury after stroke, trauma, and seizures
  • Identification of novel zinc binding motifs: enhance searching genomes for new zinc metalloenzymes.
  • Development of specific inhibitors of biologically relevant zinc metalloenzymes such as metalloproteinases (bone development, tumor invasion, etc.).
  • What is the function of metallothionein?
  • What impact does zinc dysregulation have upon zinc-modulated synaptic transmission ?
  • Examine the consequences (beneficial or otherwise) of zinc mediated inhibition of protein oxidation.
  • What role has the development of zinc finger proteins and zinc homeostatic mechanisms played in eukaryotic evolution?
  • Identify zinc-dependent transcription factors and regulated genes, the role of gene in hormone-receptor interactions, gene-dependent signal transduction pathways, and identify gene-associated signals which affect cell cycle regulation.
  • When and where does apoptosis require zinc?
  • How does zinc act in concert with other apoptotic regulators e.g., Bc1-2? Bc1-2?
  • Does increased apoptosis occur in human zinc deficiency and if so, in which tissues?
  • Are any of the clinical manifestations of zinc deficiency due to increased apoptosis?
Research questions to characterize the role of zinc in the gastrointestinal system:
  • Does zinc maintain intestinal defense systems?
  • Relationship of zinc to intestinal fluid balance.
  • Define the linkages of intestinal zinc transporters to body zinc status.
  • Is there a brush border (apical) membrane zinc transporter for enterocytes?
Research questions and directives to characterize the role of zinc in immune function:
  • What is the mechanism of zinc activation and why does zinc only induce monocytes?
  • How does zinc increase IFN-? production and what is the influence of zinc on other immunostimulants?
  • Examine zinc as an inhibitor of site-specific reactions, and explore how zinc's inhibitory effects might be useful for therapy.
Research questions or directives to characterize the role of zinc in the central nervous system:
  • What role do zinc-modulated synapses (synapses at which the boutons  release zinc) play in normal neurobehavioral control ?
  • Describe the pathophysiology of  zinc-induced neuron death.
  • Support animal-model studies-emphasizing central (hypothalamic) control of food intake and body weight regulation during zinc-related anorexia.
  • Is zinc the indicator of the presence of or cause of amyloid deposits or lesions in the brain?
  • What is the life cycle of presynaptic vesicular zinc in the CNS ?
  • Characterize regulation of zinc transporters at zinc-modulated synapses in the central nervous system.
  • What is the normal physiological function of the zinc ions that are co-released with glutamate at cerebrocortical synapses ?
  • What is the function of metallothionein-3 in the central nervous system?
  • Evaluate the effects of zinc deficiency on signal transduction pathways pertaining to anorexia and body weight regulations.
II. Research questions or directives regarding the elucidation of the details of zinc metabolism and mechanisms of zinc homeostasis at a molecular, subcellular, cellular organ/system and whole body level.
  • Evaluate mechanisms for zinc absorption and their regulation.
  • What are the effects on zinc absorption due to interactions with non-essential elements and among dietary factors?
  • What are the signals that modulate the changes in urinary and endogenous fecal excretion with changes in intake?
  • What tissues or cell types preferentially and by what mechanism retain zinc with deficiency or gain zinc with toxicity? How is this preferential retention altered with dietary factors, growth, reproduction and disease?
  • What are the effects of prior zinc status on zinc absorption?How does gene deletion or over-expression affect zinc metabolism?
  • Characterization of dietary, physiologic and pathologic factors that perturb homeostasis.
  • Undertake the characterization of processes of absorption and excretion in the gastrointestinal tract in response to range of dietary zinc and bioavailability.
  • Identification of the regulatory signals for adaptive responses.
  • Support studies linking observations of subcellular Zn transport with whole body homeostasis.
  • How does zinc enter the cell, where is it stored, how is its concentration controlled, and what is its hierarchy and method of distribution within the cell?
  • How and where is zinc uptake and distribution regulated?
  • How is zinc intake related to growth and how do requirements change with age?
  • Evaluate the physiologic and developmental regulation of zinc transporters.
  • Determine the relative metabolic importance of importers vs. exporters.
  • Evaluate how overlap of activity of other cation transporters is responsible for mineral-mineral interactions involving zinc.
III. Research questions or directives for the clarification of the epidemiology of human zinc deficiency and improved methods/strategies for the detection, prevention and management of zinc deficiency in otherwise healthy humans as well as in a wide range of disease states.
  • What are the short term and long-term consequences of transitory zinc deficiency during different developmental stages? Are there epigenetic consequences of prenatal zinc deficiency?
  • What is the role of zinc in various diseases and how do zinc requirements change depending on disease pathology, e.g. diabetes?
  • What is the role of zinc and alpha-2 macroglobulin interaction in health and Alzheimer's Disease?
  • Development of simple, useful, serum-based measure reflecting body zinc stores (like serum ferritin for iron status) and of tissue zinc deficiency (like serum transferrin receptor for iron deficiency).
IV. Research questions or directives regarding the characterization of the benefits/risks of zinc supplementation with emphasis on recognized zinc responsive biological systems including oxidative stress and host defense to infection.
 
  • Will aggressive zinc supplementation significantly reduce the destruction of the immune system that occurs in chronic diseases and dietary deficiencies where zinc is suboptimal? Will it reduce the incidence of infections, inflammatory responses and mortality in deficient hosts?
  • Can zinc be used in combination with cytokine and/or drug therapy in clinical settings to bring about even better protection of the immune system then zinc supplementation alone?
  • Will zinc supplementation bring about full repair of an immune system altered by zinc deficiency during fetal-neonatal development, pregnancy, or aging?
  • Is the use of zinc supplements associated with improved fertility, reductions in early fetal wastage and fetal malformations?
  • What are the risks associated with the use of zinc supplements prior to, and during pregnancy?
  • Support clinical studies examining nutrient supplementation during anorexia.
  • Given the observation that an early effect of zinc deficiency in the developing conceptus is oxidative damage, will the antioxidant status of an individual modulate their response to tertriatogenic insults which influence maternal-conceptus zinc transfer?
  • Examine the effects of zinc on apoptosis, particularly in ischemic injury. 
In many instances, techniques are available that will allow accelerated progress to be achieved.  In some instances however, progress will be dependent on the development of new techniques and adaptation of existing technologies to zinc-related research.