Abstract:

Mathematical and computational modeling approaches were applied to the study of four biological systems, each corresponding to a specific length scale. The four systems investigated were: (i) Molecular scale: The Fc/FcRn protein binding interaction, (ii) Cellular scale: The transferrin trafficking pathway, (iii) Multicellular scale: The prostate epithelium, and (iv) Whole-body scale: The regulation of iron uptake.

i. Molecular scale. Since the binding of Fc to the neonatal Fc receptor, FcRn, is responsible for the long half-life of IgG, one approach to extend the half-lives of therapeutic antibodies involves optimizing this interaction. To identify Fc mutations which could increase its affinity for FcRn, a computer program was developed which predicted the effects of Fc mutations on FcRn binding affinity. The program successfully recapitulated qualitative trends in the experimental binding of Fc mutants to FcRn.

ii. Cellular scale. Transferrin has been used to target therapeutics to tumors, since the transferrin receptor is overexpressed in cancers. To improve transferrin drug carrier efficacy, a mathematical model of the transferrin intracellular trafficking pathway was formulated. The model predicted that lowering the iron release rate of transferrin would increase cellular association and probability of delivering a drug, which was subsequently verified with in vitro trafficking and cytotoxicity experiments.

iii. Multicellular scale. Experimental studies suggest that cell movement may play a part in homeostasis of the prostate epithelium, and certain genes frequently altered in prostate cancer are known to regulate cell movement. To investigate the role of prostate cell movement, an agent-based model of the prostate epithelium was established. Simulations of cell movement behaviors within a three-dimensional reconstruction of a prostate duct were evaluated against experimental observations.

iv. Whole-body scale. To highlight the importance of recent findings in the study of iron homestasis, and to clarify the role of recent findings in the study of iron homeostasis in the context of an overall model of iron regulation, a compartmental model of iron homeostasis was developed. It was shown that the characteristics of hereditary hemochromatosis could be reproduced by altering the values of molecular parameters in a fashion consistent with the effects of mutations in the HFE gene.