Type of Document Dissertation Author Conrad, Emery David Author's Email Address firstname.lastname@example.org URN etd-04272006-110409 Title Bifurcation Analysis and Qualitative Optimization of Models in Molecular Cell Biology with Applications to the Circadian Clock Degree PhD Department Mathematics Advisory Committee
Advisor Name Title Rogers, Robert C. Committee Chair Tyson, John J. Committee Co-Chair Laubenbacher, Reinhard C. Committee Member Phillips, John B. Committee Member Renardy, Michael J. Committee Member Keywords
- circadian rhythms
- parameter optimization
- bifurcation analysis
Date of Defense 2006-04-14 Availability unrestricted Abstract
Circadian rhythms are the endogenous, roughly 24-hour rhythms that coordinate an organism's interaction with its cycling environment. The molecular mechanism underlying this physiological process is a cell-autonomous oscillator comprised of a complex regulatory network of interacting DNA, RNA and proteins that is surprisingly conserved across many different species. It is not a trivial task to understand how the positive and negative feedback loops interact to generate an oscillator capable of a) maintaining a 24-hour rhythm in constant conditions; b) entraining to external light and temperature signals; c) responding to pulses of light in a rather particular, predictable manner; and d) compensating itself so that the period is relatively constant over a large range of temperatures, even for mutations that affect the basal period of oscillation.
Mathematical modeling is a useful tool for dealing with such complexity, because it gives us an object that can be quickly probed and tested in lieu of the experiment or actual biological system. If we do a good job designing the model, it will help us to understand the biology better by predicting the outcome of future experiments. The difficulty lies in properly designing a model, a task that is made even more difficult by an acute lack of quantitative data. Thankfully, our qualitative understanding of a particular phenomenon, i.e. the observed physiology of the cell, can often be directly related to certain mathematical structures. Bifurcation analysis gives us a glimpse of these structures, and we can use these glimpses to build our models with greater confidence.
In this dissertation, I will discuss the particular problem of the circadian clock and describe a number of new methods and tools related to bifurcation analysis. These tools can effectively be applied during the modeling process to build detailed models of biological regulatory with greater ease.
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