TitleA systems biology approach for assessing corticosteroid activity
NameYang, Eric H. (author), Roth, Charles (chair), Androulakis, Ioannis (internal member), Yarmush, Martin (internal member), Moghe, Prahbas (internal member), Ierapetritou, Marianthi (outside member), Rutgers University, Graduate School - New Brunswick,
DescriptionGlucocorticosteroids are endogenous hormones that are produced in the adrenal gland and are responsible for the regulation of glucose metabolism. However, corticosteroids are also utilized therapeutically for the suppression of the immune system as well as the treatment of inflammation. Despite their immunosuppressive and anti-inflammatory role, long term use of corticosteroids is problematic due to severe side effects. Deciphering a comprehensive mechanism of corticosteroid activity might offer valuable clues for mitigating the adverse side effects.
To accomplish this task we have leveraged high throughput experimental methods such as mRNA microarrays as well as a new technique for measuring transcription factor activity based on a novel technology, namely the Living Cell Array. However, due to the large amount of information which is generated by these methods, it is imperative that automated methods be developed to identify the critical pieces of information present in the large amount of data generated. Our primary focus was on characterizing the dynamics of transcriptional response and to further isolate relevant regulatory structures.
Our analysis is based on in vivo (liver) measurements of a rat model as well as hepatocyte cultures in the living cell array. Major findings of this work suggest that the anti-inflammatory effect of corticosteroids appear to be a transient phenomenon under a sustained infusion of corticosteroids, whereas the metabolic effects of corticosteroids appear to be ongoing in concordance with sustained stimuli via the drug. Furthermore, it is suggested that the monomeric form or the glucocorticosteroid receptor was active. Specifically, given the consensus sequence associated with the dimeric form of the corticosteroid receptor, there is evidence that a monomeric form of the glucocorticosteroid will bind, and more importantly cause the transcription of said gene. Finally, evidence is obtained that the anti-inflammatory effects of corticosteroids aside from being transient are regulated by a feedback loop.
A model of corticosteroid activity is finally proposed which utilizes two separate and active forms of the glucocorticosteroid receptor. The advantage of this model over the currently accepted one is that it is able to replicate the response of the system to corticosteroids with a very simple mechanistic explanation. The model recreates both the response of the host to an injection as well as infusion of corticosteroid, as well as the circadian variation of gene expression due to the circadian oscillations of endogenous corticosteroid levels.
NoteIncludes bibliographical references (p. 227-234)
Noteby Eric H. Yang
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
RightsThe author owns the copyright to this work.