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Structure-binding activity relations of amphiphilic polymers and macrophage scavenger receptors

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TypeOfResource
Text
TitleInfo (ID = T-1)
Title
Structure-binding activity relations of amphiphilic polymers and macrophage scavenger receptors
SubTitle
implications for therapeutic inhibition of atherosclerosis
Identifier
ETD_2851
Identifier (type = hdl)
http://hdl.rutgers.edu/1782.1/rucore10001600001.ETD.000056724
Language
LanguageTerm (authority = ISO639-2); (type = code)
eng
Genre (authority = marcgt)
theses
Subject (ID = SBJ-1); (authority = RUETD)
Topic
Chemical and Biochemical Engineering
Subject (ID = SBJ-2); (authority = ETD-LCSH)
Topic
Atherosclerosis--Treatment
Subject (ID = SBJ-3); (authority = ETD-LCSH)
Topic
Low density lipoproteins
Subject (ID = SBJ-4); (authority = ETD-LCSH)
Topic
Cardiovascular receptors
Subject (ID = SBJ-5); (authority = ETD-LCSH)
Topic
Molecules--Models
Abstract (type = abstract)
Scavenger receptors mediate the uptake of oxidized low density lipoprotein (oxLDL), leading to cholesterol accumulation and the development of atherosclerosis. A promising avenue of interest in the treatment of cardiovascular disease is the use of a scavenger receptor inhibitor. To this end, a series of polymers were designed based on a mucic acid backbone, aliphatic acid arms and polyethylene glycol tail. Molecular modeling and docking approaches were used to understand the structure-activity relationship (SAR) between the polymers and scavenger receptor class A (SR-A). The polymers containing hydrophobic-bound carboxylate groups were the most favorable binders to the SR-A model as well as the most efficient inhibitors of oxLDL accumulation. Mutant SR-A models were generated by replacing charged residues with alanine. All charged residues in the region were necessary, with Lys60, Lys63 and Lys66 having the greatest effect on binding. However, binding was not mediated by charge alone and the polymer hydrophobic domain adjacent to the carboxylate group was found to be essential. Based on these findings from Chapter 2, the next chapter focused on the polymer backbone. Polymer models were designed to investigate the influence of backbone stereochemistry, cyclic versus linear backbone, and aromatic versus aliphatic backbone. Molecular modeling and docking results indicate the ability of the backbone to favorably position the side chains and “lock” the ligand into position. In vitro results followed those seen in the modeling predictions, with two polymers showing promise. Thus, minute changes in polymer structures can sensitively affect SR-A binding affinities and modulate the competitive inhibition of oxLDL uptake. This thesis also investigated the potential of amphiphilic polymers to target scavenger receptors and deliver a hydrophobic model drug reversing cholesterol accumulation. The polymers encapsulated hydrophobic agonist (GW3965) against nuclear Liver-X receptor α (LXR), which significantly increased the drug uptake over non-polymer delivery. In combination with the encapsulated LXR-agonist, the polymers reduced oxLDL by 88% in vitro. Thus, the thesis findings suggest that the system of amphiphilic polymers exhibited significant tunability for scavenger receptor targeting, which can be exploited both for inhibition of cholesterol uptake as well as modulating cholesterol trafficking.
PhysicalDescription
Form (authority = gmd)
electronic resource
Extent
xi, 125 p. : ill.
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application/pdf
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text/xml
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
Note (type = vita)
Includes vita
Note (type = statement of responsibility)
by Nicole M. Plourde
Name (ID = NAME-1); (type = personal)
NamePart (type = family)
Plourde
NamePart (type = given)
Nicole M.
NamePart (type = date)
1982-
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author
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Nicole Plourde
Name (ID = NAME-2); (type = personal)
NamePart (type = family)
Moghe
NamePart (type = given)
Prabhas V
Role
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chair
Affiliation
Advisory Committee
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Prabhas V Moghe
Name (ID = NAME-3); (type = personal)
NamePart (type = family)
Roth
NamePart (type = given)
Charles
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internal member
Affiliation
Advisory Committee
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Charles Roth
Name (ID = NAME-4); (type = personal)
NamePart (type = family)
Uhrich
NamePart (type = given)
Kathryn E
Role
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internal member
Affiliation
Advisory Committee
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Kathryn E Uhrich
Name (ID = NAME-5); (type = personal)
NamePart (type = family)
Welsh
NamePart (type = given)
William J
Role
RoleTerm (authority = RULIB)
outside member
Affiliation
Advisory Committee
DisplayForm
William J Welsh
Name (ID = NAME-1); (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (ID = NAME-2); (type = corporate)
NamePart
Graduate School - New Brunswick
Role
RoleTerm (authority = RULIB)
school
OriginInfo
DateCreated (qualifier = exact)
2010
DateOther (qualifier = exact); (type = degree)
2010-10
Place
PlaceTerm (type = code)
xx
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
Location
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NjNbRU
Identifier (type = doi)
doi:10.7282/T31V5DQ9
Genre (authority = ExL-Esploro)
ETD doctoral
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RightsDeclaration (AUTHORITY = GS); (ID = rulibRdec0006)
The author owns the copyright to this work.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
RightsHolder (ID = PRH-1); (type = personal)
Name
FamilyName
Plourde
GivenName
Nicole
Role
Copyright Holder
RightsEvent (ID = RE-1); (AUTHORITY = rulib)
Type
Permission or license
DateTime
2010-09-08 13:22:05
AssociatedEntity (ID = AE-1); (AUTHORITY = rulib)
Role
Copyright holder
Name
Nicole Plourde
Affiliation
Rutgers University. Graduate School - New Brunswick
AssociatedObject (ID = AO-1); (AUTHORITY = rulib)
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.
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ETD
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application/pdf
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application/x-tar
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3717120
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