Jignesh H. Parmar
Profile Url: jignesh-h--parmar
Researcher at Ctr for Quantitative Medicine & Dept of Cell Biology, University of Connecticut School of Medicine
BMC Systems Biology, 2017-05-18
Background: Iron is an essential element of most living organisms but is a dangerous substance when poorly liganded in solution. The hormone hepcidin regulates the export of iron from tissues to the plasma contributing to iron homeostasis and also restricting its availability to infectious agents. Disruption of iron regulation in mammals leads to disorders such as anemia and hemochromatosis, and contributes to the etiology of several other diseases such as cancer and neurodegenerative diseases. Here we test the hypothesis that hepcidin alone is able to regulate iron distribution in different dietary regimes in the mouse using a computational model of iron distribution calibrated with radioiron tracer data. Results: A model was developed and calibrated to the data from adequate iron diet, which was able to simulate the iron distribution under a low iron diet. However simulation of high iron diet shows considerable deviations from the experimental data. Namely the model predicts more iron in red blood cells and less iron in the liver than what was observed in experiments. Conclusions: These results suggest that hepcidin alone is not sufficient to regulate iron homeostasis in high iron conditions and that other factors are important. The model was able to simulate anemia when hepcidin was increased but was unable to simulate hemochromatosis when hepcidin was suppressed, suggesting that in high iron conditions additional regulatory interactions are important.
Molecular Microbiology, 2018-09-16
Biological systems require precise copper homeostasis enabling metallation of cuproproteins while preventing metal toxicity. In bacteria, sensing, transport and storage molecules act in coordination to fulfill these roles. However, there is not yet a kinetic schema explaining the system integration. Here, we report a model emerging from experimental and computational approaches that describes the dynamics of copper distribution in Pseudomonas aeruginosa. Based on copper uptake experiments, a minimal kinetic model describes well the copper distribution in the wild type bacteria but is unable to explain the behavior of the mutant strain lacking CopA1, a key Cu+ efflux ATPase. The model was expanded through an iterative hypothesis-driven approach, arriving to a mechanism that considers the induction of compartmental pools and the parallel function of CopA and Cus efflux systems. Model simulations support the presence of a periplasmic copper storage with a crucial role under dyshomeostasis conditions in P. aeruginosa. Importantly, the model predicts not only the interplay of periplasmic and cytoplasmic pools but also the existence of a threshold in the concentration of external copper beyond which cells lose their ability to control copper levels.
PLOS Computational Biology, 2019-01-04
It is well known that iron is an essential element for life but is toxic when in excess or in certain forms. Accordingly there are many diseases that result directly from either lack or excess of iron. Iron has also been associated with a wide range of other diseases and may have an important role in aging. Yet many molecular and physiological aspects of iron regulation have only been discovered recently and others are still awaiting elucidation. In the last 18 years, after the discovery of the hormone hepcidin, many details of iron regulation have become better understood and a clearer picture is starting to emerge, at least in qualitative terms. However there is still no good quantitative and dynamic description of iron absorption, distribution, storage and mobilization that agrees with the wide array of phenotypes presented in several iron-related diseases. The present work addresses this issue by developing a mathematical model of iron distribution in mice that was calibrated with existing ferrokinetic data and subsequently validated against data from a series of iron disorders, such as hemochromatosis, β-thalassemia, atransferrinemia and anemia of inflammation. To adequately fit the ferrokinetic data required including the following mechanisms: a) the role of transferrin in deliving iron to tissues, b) the induction of hepcidin by high levels of transferrin-bound iron, c) the ferroportin-dependent hepcidin-regulated iron export from tissues, d) the erythropoietin regulation of erythropoiesis, and e) direct NTBI uptake by the liver. The utility of such a model to simulate disease interventions was demonstrated by using it to investigate the outcome of different schedules of transferrin treatment in β-thalassemia. The present model is a successful step towards a comprehensive mathematical model of iron physiology incorporating cellular and organ level details.