Semester

Fall

Date of Graduation

2010

Document Type

Thesis

Degree Type

MS

College

Statler College of Engineering and Mineral Resources

Department

Chemical and Biomedical Engineering

Committee Chair

David J Klinke

Abstract

Chronic diseases, cancers and diabetes are associated with dysregulation of many biochemical cues. These biochemical cues are proteins that regulate cellular activity migration and death. The synthesis of these proteins is regulated by nuclear transcription factors. One of the most studied transcription factor is nuclear factor kappa B (NFkappaB). Many different proteins have been identified that regulate the activity of NFkappaB. Yet, how these proteins regulate NFkappaB is still unclear.;Understanding the regulation of NFkappaB is important for developing drugs to treat these diseases. Our long term goal is to understand the mechanisms that regulate NFkappaB activity. The goal of this research is to identify how NFkappaB activity is regulated. As a model system, we will use LPS to stimulate macrophage cells with or without 3, 4-dichloropropionanilide (DCPA) treatment. DCPA is a post-emergent herbicide used for controlling weeds in rice crops. Exposure to DCPA causes increases in liver and spleen weight demonstrated by toxicity study on rats. Previous study in our lab showed that DCPA could modulate NFkappaB activity. Our central hypothesis is that a mathematical model can be used to infer the regulation steps that are altered following DCPA treatment. To test our central hypothesis, we performed the following specific aim: Establish that NFkappaB is differentially regulated by IkappaBalpha and IkappaBbeta and that these proteins are in turn differentially regulated by DCPA. Moreover, a mathematical model was used to establish observed dynamics of NFkappaB activities. Our working hypothesis is that an ordinary differential equation (ODE)-based model that includes NFkappaB regulation by IkappaBalpha proteins can capture the observed dynamics. Furthermore, we used an empirical Bayesian approach to establish confidence in model parameters. Then, we included IkappaBbeta in the model to more realistically describe the regulation of NFkappaB activity in macrophages.;We expect that the results of this research will lead to greater understanding of the regulatory mechanism of NFkappaB signaling pathway in macrophages and have important implication for human health. This improved understanding may also inspire new ideas to treat these diseases.

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