RUcore: Rutgers University Community Repository
A systems biology approach for assessing corticosteroid activity
Descriptive
TypeOfResource
Text
TitleInfo
(ID = T-1)
Title
A systems biology approach for assessing corticosteroid activity
Identifier
ETD_1256
Identifier
(type = hdl)
http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.000050478
Language
LanguageTerm
(authority = ISO639-2);
(type = code)
eng
Genre
(authority = marcgt)
theses
Subject
(ID = SBJ-1);
(authority = RUETD)
Topic
Biomedical Engineering
Subject
(ID = SBJ-1);
(authority = ETD-LCSH)
Topic
Andrenocortical hormones
Abstract
Glucocorticosteroids 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.
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.
PhysicalDescription
Extent
xv, 237 p. : ill.
InternetMediaType
application/pdf
InternetMediaType
text/xml
Note
(type = degree)
Ph.D.
Note
(type = bibliography)
Includes bibliographical references (p. 227-234)
Note
(type = statement of responsibility)
by Eric H. Yang
Name
(ID = NAME-1);
(type = personal)
NamePart
(type = family)
Yang
NamePart
(type = given)
Eric H.
Role
RoleTerm
(authority = RULIB);
(type = )
author
DisplayForm
Eric H. Yang
Name
(ID = NAME-2);
(type = personal)
NamePart
(type = family)
Roth
NamePart
(type = given)
Charles
Role
RoleTerm
(authority = RULIB);
(type = )
chair
Affiliation
Advisory Committee
DisplayForm
Charles Roth
Name
(ID = NAME-3);
(type = personal)
NamePart
(type = family)
Androulakis
NamePart
(type = given)
Ioannis
Role
RoleTerm
(authority = RULIB);
(type = )
internal member
Affiliation
Advisory Committee
DisplayForm
Ioannis Androulakis
Name
(ID = NAME-4);
(type = personal)
NamePart
(type = family)
Yarmush
NamePart
(type = given)
Martin
Role
RoleTerm
(authority = RULIB);
(type = )
internal member
Affiliation
Advisory Committee
DisplayForm
Martin Yarmush
Name
(ID = NAME-5);
(type = personal)
NamePart
(type = family)
Moghe
NamePart
(type = given)
Prahbas
Role
RoleTerm
(authority = RULIB);
(type = )
internal member
Affiliation
Advisory Committee
DisplayForm
Prahbas Moghe
Name
(ID = NAME-6);
(type = personal)
NamePart
(type = family)
Ierapetritou
NamePart
(type = given)
Marianthi
Role
RoleTerm
(authority = RULIB);
(type = )
outside member
Affiliation
Advisory Committee
DisplayForm
Marianthi Ierapetritou
Name
(ID = NAME-1);
(type = corporate)
NamePart
Rutgers University
Role
RoleTerm
(authority = RULIB);
(type = )
degree grantor
Name
(ID = NAME-2);
(type = corporate)
NamePart
Graduate School - New Brunswick
Role
RoleTerm
(authority = RULIB);
(type = )
school
OriginInfo
DateCreated
(point = );
(qualifier = exact)
2008
DateOther
(qualifier = exact);
(type = degree)
2008-10
Place
PlaceTerm
(type = code)
xx
Location
PhysicalLocation
(authority = marcorg)
NjNbRU
RelatedItem
(type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier
(type = RULIB)
ETD
RelatedItem
(type = host)
TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier
(type = local)
rucore19991600001
Identifier
(type = doi)
doi:10.7282/T3KD1Z65
Genre
(authority = ExL-Esploro)
ETD doctoral
Back to the top
Rights
RightsDeclaration
(AUTHORITY = GS);
(ID = rulibRdec0006)
The author owns the copyright to this work.
Copyright
Status
Copyright protected
Availability
Status
Open
RightsEvent
(AUTHORITY = rulib);
(ID = 1)
Type
Permission or license
Detail
Non-exclusive ETD license
AssociatedObject
(AUTHORITY = rulib);
(ID = 1)
Type
License
Name
Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
Back to the top
Technical
ContentModel
ETD
MimeType
(TYPE = file)
application/pdf
MimeType
(TYPE = container)
application/x-tar
FileSize
(UNIT = bytes)
2375680
Checksum
(METHOD = SHA1)
cf1fdcc51c64a8be0783117b80af1a797efabcdf
Back to the top
Statistical Profile