David W. Killilea, Senior Scientist
RESEARCH INTERESTSThe common denominator of my research interests is the regulation of metal homeostasis. Both suboptimal levels of nutritive metals and exposure to toxic metals cause cellular dysfunction. Conversely, changes in cell physiology (e.g. senescence) alter normal metal homeostasis. I am interested in understanding these metabolic changes and defining the subsequent functional consequences. My research program is currently focused in the following areas:
Targets and Consequences of Magnesium Deficiency The consequences of severe micronutrient deficiencies are well described, but much less is known about chronic, marginal deficiencies which are much more common in the US population [ILLUSTRATIONS]. Magnesium is such a nutrient, as widespread moderate deficiency exists, yet the health costs are largely unknown. Magnesium deficiency in humans has recently been associated with diabetes, hypertension, and cardiovascular disease. We have shown that chronic magnesium deficiency in human cells can undermine mitochondrial function and cellular senescence, suggesting fundamental changes in cellular phenotype when magnesium is limiting.
Iron Homeostasis During Aging and Cellular Senescence Although iron is a required nutrient, imbalances in iron levels can cause oxidative stress and cellular injury. Studies indicate that iron accumulates in numerous tissues with age, especially in age-related diseases; recent evidence suggests iron chelation reduces morbidities and even extends lifespan in several animal models. We have shown that iron also accumulates as a consequence of normal senescence in some human cells. This may be partly explained by uncoupling of the iron sensing and regulatory mechanisms, thus serving as a novel target for pharmaceutical/nutriceutical action.
Quantitative Metallomics and Metalloproteomics Typical reductionist paradigms dissect key regulatory components of metal homeostasis, but the crosstalk between regulatory pathways of multiple metals often remains underappreciated. Thus, a systems biology approach is also necessary to fully characterize relationships between metals. In collaboration with scientists at Lawrence Livermore National Laboratory, we are characterizing entire metallomes and metalloproteomes to detect unique changes in global proteomic patterns, identify new biomarkers of clinical utility, and reveal novel targets of metal binding for both nutritive and non-nutritive metals.
Killilea Biosketch
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