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Engineering embryonic stem cells for myelin cell therapy

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TypeOfResource
Text
TitleInfo (ID = T-1)
Title
Engineering embryonic stem cells for myelin cell therapy
SubTitle
PartName
PartNumber
NonSort
Identifier
ETD_1624
Identifier (type = hdl)
http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.000051395
Language (objectPart = )
LanguageTerm (authority = ISO639-2); (type = code)
eng
Genre (authority = marcgt)
theses
Subject (ID = SBJ-1); (authority = RUETD)
Topic
Physiology and Integrative Biology
Subject (ID = SBJ-2); (authority = ETD-LCSH)
Topic
Myelin genes
Subject (ID = SBJ-3); (authority = ETD-LCSH)
Topic
Cellular therapy
Abstract
Cell replenishment using stem cell-derived transplants holds great promise for therapy in human disease. However, clinical therapeutics in the central nervous system (CNS) requires targeted migration for lesion repair. For CNS grafts, homing the graft population to the appropriate site for tissue repair is non trivial since surgical access to wound is not risk free. Our objective is to modify stem cells to generate lineage specified CNS glia that 'home' into lesions, focusing on myelin repair for multiple sclerosis and spinal cord injury. Myelin protects neuronal axons, and in pre-clinical models ES-derived OL progenitor cell (OPC) grafts can regenerate myelin forming oligodendrocytes (OLs) and rescue the phenotype of myelin-defective mice. Our studies focus on engineering ES cells to expresss PDGFRα, the trans-membrane receptor for Platelet-Derived Growth Factor, which directs OPC migration during brain development. Prior work identified a 'rheostat' function for PDGFRα, with low levels of PDGF activating PI3K to in initiate migration and high levels activating PLCγ to inhibit migration. This predicts that PLCγ-uncoupled receptors would direct ES-derived OPCs toward PDGF infused brain lesions. We addressed the rheostat model by engineering mouse ES cells to express wild-type and signal transduction mutant versions of PDGFRα. First we generated a medium cocktail named '2i5S' that allows the the long-term expansion of mouse ES cell lines, which is optimal for our engineering experiments. Next we introduced PDGFRα transgenes into mES cells in vitro. A very low number of stable ES transformants were obtained after transfection, and this directed us towards using a set of vectors (TRE.PDGFRα) with tetracycline inducible promoter for control of transgene expression. Lastly, we used myelin mutant shiverer mice to evaluate the potential of ES-derived OPCs to generate myelin in vivo. Our results showed substantial improvements in both motor function and longevity in animals with 7% of ESwtderived cells present in the pup. Therefore this suggests that 7% ES-derived stem cell engraftment is the minimal level that is required for functional cell replacement therapy.
PhysicalDescription
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electronic resource
Extent
viii, 42 p. : ill.
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application/pdf
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text/xml
Note (type = degree)
M.S.
Note (type = bibliography)
Includes bibliographical references (p. 39-42)
Note (type = statement of responsibility)
by Dorota Sadowski
Name (ID = NAME-1); (type = personal)
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Sadowski
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Dorota
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author
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Dorota Sadowski
Name (ID = NAME-2); (type = personal)
NamePart (type = family)
McKinnon
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Randall
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chair
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Advisory Committee
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Randall D. McKinnon
Name (ID = NAME-3); (type = personal)
NamePart (type = family)
Shi
NamePart (type = given)
Yufang
Role
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internal member
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Advisory Committee
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Yufang Shi
Name (ID = NAME-4); (type = personal)
NamePart (type = family)
Pan
NamePart (type = given)
Zui
Role
RoleTerm (authority = RULIB); (type = )
internal member
Affiliation
Advisory Committee
DisplayForm
Zui Pan
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)
2009
DateOther (qualifier = exact); (type = degree)
2009-05
Place
PlaceTerm (type = code)
xx
Location
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NjNbRU
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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/T3F18ZZN
Genre (authority = ExL-Esploro)
ETD graduate
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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)
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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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Technical

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ETD
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application/x-tar
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1157120
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