Research Project

Modeling sterol regulatory system

Validating mathematical models of the yeast sterol regulatory pathway.

Disorders in human cholesterol regulation can lead to heart disease, the leading cause of death in the United States. We seek to understand the cholesterol regulatory system better by studying the homologous system in fission yeast (Schizosaccharomyces pombe). Using biochemical experiments – done in collaboration with Peter Espenshade of the Department of Cell Biology, JH School of Medicine, and principles from control engineering and dynamical system theory, we are developing, analyzing and validating mathematical models of the yeast sterol regulatory pathway. Our goal is to understand how the components of this pathway work together to achieve several performance objectives, including the maintenance of sterol levels under changing environmental conditions. We expect that this knowledge will lead to improvements in the treatment of cholesterol-related human diseases.

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Model analysis shows the contribution of the two regulatory functions of Ofd1 to Sre1N regulation. (A, B) We computed the rate of Sre1N production (red surface) and degradation (blue surface) in the model as a function of oxygen and Sre1N levels. sre1N+ mRNA and Ofd1 protein levels are taken to be at steady state. (C, D) We repeated this for the model without regulated DNA binding. This changes the Sre1N production rate but not the degradation rate. (E, F) We also repeated this for the model without regulated degradation. In this case the Sre1N production rates are the same as in the unmodified model, but the degradation rates are different. (B, D, F) Bottom, the projection of the steady-state curve—the points at which Sre1N production and degradation rates are equal—onto the oxygen-Sre1N plane. The regulation ratio is the ratio of total Sre1N under anoxia (0.01% oxygen) to that under normoxia (21% oxygen)

Some publications related to this work are:
1. Porter JR, Burg JS, Espenshade PJ, Iglesias PA. Identifying a static nonlinear structure in a biological system using noisy, sparse data. J Theor Biol. 300:232-41, 2012.
2. Porter JR, Lee CY, Espenshade PJ, Iglesias PA. Regulation of SREBP during hypoxia requires Ofd1-mediated control of both DNA binding and degradation. Mol Biol Cell. 23:3764-74, 2012.
3. Porter JR, Burg JS, Espenshade PJ, Iglesias PA. Ergosterol regulates sterol regulatory element binding protein (SREBP) cleavage in fission yeast. J Biol Chem. 285:41051-61, 2010.

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