An Overview





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Metals have complex, interconnected, and fundamental roles within human metabolism. (1) Nutritional metals are tightly regulated by coordinate molecular pathways that drive dynamic systemic processes. Many of these mineral nutrients are deficient in our dietary patterns, resulting in metabolic defects and chronic disease. (2) Conversely, toxic metals can foul metabolic processes often by masquerading as mineral nutrients, but fail to provide the correct binding or regulatory activity. Numerous toxic metals infiltrate our environment leading to low-level but long-term exposures. Thus, development of improved biomarkers and effective countermeasures remains urgently needed. (3) Finally, some metals still have unknown actions within our systems, despite many in this group being proposed to have beneficial functions. Characterizing these activities will reveal new insight into our complex metabolism and new targets for disease intervention. The following active projects address key aspects of metal homeostasis and metabolism.

Determine the consequences of imbalanced nutritional metals at the cellular and molecular level. Approximately ten metal micronutrients are known to be essential. Significant morbidities result when levels of these mineral nutrients are low, either from diet or metabolic abnormalities. The RDAs reflect the minimum levels of micronutrients to avoid acute disease, but it is now appreciated that long-term damage can occur when micronutrient levels are moderately low, even if near the RDAs (PMID: 16102804). Thus, determining the amount of each micronutrient for optimal well-being ought to be the real public health goal. We are dissecting the molecular and cellular processes affected by moderate metal micronutrient deficiencies in order to understand what amounts of micronutrients are required for a healthy lifespan. Additionally, we are trying to understand the ratios within metal micronutrient groups that seem to be key for optimal nutritional balance. This work was supported in part by grants from the DOD/CDMRP Program (W81XWH-05-1-0106), Almond Board of California, and Bruce & Giovanna Ames Foundation.

  • Killilea DW, et al. Iron accumulation during cellular senescence in human fibroblasts in vitro. Antioxid Redox Signal, 2003. PMID: 14580305
  • Killilea AN, et al. Zinc deficiency reduces paclitaxel efficacy in LNCaP prostate cancer cells. Cancer Lett, 2007. PMID: 17905512
  • Killilea DW and Ames, BN. Magnesium deficiency accelerates cellular senescence in cultured human fibroblasts. PNAS, 2008. PMID: 18391207

Understand the effects of toxic metal in cellular and simple invertebrate systems. The effects of many toxic metals are known at acutely high levels, but much less is understood about low-level exposures over a prolonged period of time, although the latter should be the more prevalent concern in terms of populations affected and healthcare dollars spent. Much of our work in this area has been in collaboration with investigators at the Buck Institute for Research in Aging, where metal toxicity has been tied to aging and aging-related disease. We have taken advantage of the powerful invertebrate animal models that provide an enormous set of genetic and pharmacological tools. This work was supported in part by several NIH grants (AG021069, AG022868, AG042053, & NS050789) and the American Federation for Aging Research.

  • McColl G, et al. Pharmacogenetic analysis of lithium-induced delayed aging in C elegans. J Biol Chem, 2008. PMID: 17959600
  • Page KE, et al. Aluminium exposure disrupts elemental homeostasis in C elegans. Metallomics, 2012. PMID: 22534883
  • Angeli S, et al. Manganese disturbs metal and protein homeostasis in C elegans. Metallomics, 2014. PMID: 25057947

Reveal the role of trace metals in kidney stone disease. Kidney stones manifest in approximately 10% of the US population, with increasing incidence and penetrance into previously unaffected populations. After several decades, few medications or prevention strategies have been developed, owing to a lack of basic under-standing of the biomineralization processes. We have recently discovered that trace metals, especially zinc, have a surprisingly important role in stone formation. Therefore, we have established an extraordinary multidisciplinary team of clinical, researchers, chemists, material scientists, and computational experts to characterize the impact of trace metals in kidney stone disease from all possible directions. This work was supported in part by several NIH grants (DK091727, DK100863, & K12-DK-07-006), the American Federation for Aging Research, the California Urology Foundation.

  • Chi T, et al. (2015) A Drosophila Model Identifies a Critical Role for Zinc Physiology in Initiating Kidney Stone Disease. PLoS One, 2015. PMID: 25970330
  • Killilea DW, et al. (2015) Elemental Content of Calcium Oxalate Stones from a Canine Model of Urinary Stone Disease. PLoS One, 2015.  PMID: 26066810
  • Ramaswamy K*, Killilea DW*, et al. The elementome of calcium-based urinary stones and its role in urolithiasis. Nature Rev Urol, 2015 PMID: 26334088

Discover new metal-metalloprotein relationships and aging-induced dysregulation. Aberrant metal imbalances have been identified in several age-related diseases, yet little is known as to how the regulation of these metals is altered during normal aging. Moreover, the crosstalk and compensatory mechanisms between metal homeostatic pathways are greatly underappreciated. In collaborative work with Lawrence Livermore National Laboratory, we are conducting a systems biology studies to solve the metallome and metalloproteome from specific biological targets in order to detect unique changes in metal patterns, reveal novel targets of metal binding, and identify new biomarkers of clinical utility to combat age-related diseases. This work was supported in part by two NIH grants (GM074819 and AG025944).

  • Grant PG, et al. Quantitative Metalloproteomics in Human Erythrocytes. Metals in Biology, Gordon Research Conference, Ventura, CA, 2006. 
  • Young NL, et al. Steady-state asymmetric nanospray dual ion source for accurate mass determination within a chromatographic separation. Anal Chem, 2007. PMID: 17614364

Characterize altered metal homeostasis during disease states. Due to our expertise in quantifying metal homeostasis in diverse biological systems, we have been asked to participate in team studies with numerous laboratories studying a variety of important disease states. These studies were most often focused on zinc or cadmium, and their affiliated metalloproteins. This work was supported in part by multiple federal and private grants to the corresponding authors.

  • Liu MJ, et al. Zinc deficiency augments leptin production and exacerbates macrophage infiltration into adipose tissue in mice fed a high-fat diet. J Nutr, 2013. PMID: 23700340
  • Engle-Stone R, et al. Stunting Prevalence, Plasma Zinc Concentrations, and Dietary Zinc Intakes in a Nationally Representative Sample Suggest a High Risk of Zinc Deficiency Among Women and Young Children in Cameroon. J Nutr, 2014. PMID: 24453129
  • Hung YH, et al. Altered transition metal homeostasis in Niemann-Pick disease, Type C. Metallomics, 2014. PMID: 24343124
  • Hassan F, et al. Accumulation of metals in GOLD4 COPD lungs is associated with decreased CFTR levels. Respir Res, 2014. PMID: 24957904

Revised: Friday, April 7, 2017 10:48 AM



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