Understanding Cancer and Metabolic Disease through Singularity Analysis of the AKT Pathway

The purpose of this research was to gain insights into the relationship and connection between cancer and other metabolic diseases. There has been clinical evidence supporting this connection and it is thought that it is likely due to the complex network of interactions, involving a common set of biomolecules. Scientists have identified the AKT, also known as protein kinase B, pathway as an important pathway for multiple cellular processes. The research extends an existing model of this pathway by including a more realistic negative feedback and incorporating all intermediate substrates that were ignored in previous models. By applying singularity and bifurcation analysis, the phenotypes constrained by the signaling pathway were identified and mapped onto the parameter space, which include cancer and certain metabolic diseases. By considering physiologic properties such as sensitivity, robustness and adaptivity that are necessary for the AKT pathway to efficiently sense growth factors and nutrients, the region of normal response was located. It was revealed that in order to optimize these properties, the intracellular concentration of the AKT protein must be sufficiently high to saturate its enzymes. Furthermore, the strength of the positive feedback must be stronger than that of the negative feedback. The analysis illuminates the parameter space and reveals system-level mechanisms in regulating biological functions and how their deregulation may lead to the development of diseases. The analytical expressions along with numerical calculations summarize the synergistic interactions among many molecules, which provide predictions to concentrations of various substrates. These concentrations can be experimentally verified and can lead to insights into cancer therapies.

Author

• Ishizuka, Yoshihisa

Language

• en

Date created

• 2012

Type of Work

• Dissertation

License

• All rights reserved

Rights statement

• In Copyright

GW Unit

• Physics

Degree

• Ph.D.

Advisor

• Zeng, Chen
• Wang, Guanyu

Committee Member(s)

• Qiu, Xiangyun
• Peng, Weiqun
• Simha, Rahul
• Lee, Frank X
• Cressman, John R

Persistent URL

•  https://scholarspace.library.gwu.edu/etd/rf55z792v