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The generation and characterization of a human induced pluripotent stem cell model for the tuberous sclerosis complex

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TitleInfo
Title
The generation and characterization of a human induced pluripotent stem cell model for the tuberous sclerosis complex
Name (type = personal)
NamePart (type = family)
Zucco
NamePart (type = given)
Avery
NamePart (type = date)
1990-
DisplayForm
Avery Zucco
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
D'Arcangelo
NamePart (type = given)
Gabriella
DisplayForm
Gabriella D'Arcangelo
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
chair
Name (type = personal)
NamePart (type = family)
Hart
NamePart (type = given)
Ronald
DisplayForm
Ronald Hart
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Dreyfus
NamePart (type = given)
Cheryl
DisplayForm
Cheryl Dreyfus
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Roko-Rasin
NamePart (type = given)
Mladen
DisplayForm
Mladen Roko-Rasin
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Jacinto
NamePart (type = given)
Estella
DisplayForm
Estella Jacinto
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
outside member
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
NamePart
School of Graduate Studies
Role
RoleTerm (authority = RULIB)
school
TypeOfResource
Text
Genre (authority = marcgt)
theses
OriginInfo
DateCreated (qualifier = exact)
2018
DateOther (qualifier = exact); (type = degree)
2018-10
CopyrightDate (encoding = w3cdtf)
2018
Place
PlaceTerm (type = code)
xx
Language
LanguageTerm (authority = ISO639-2b); (type = code)
eng
Abstract (type = abstract)
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by the mutation of either the TSC1 or TSC2 genes and characterized by the presence of benign cortical lesions known as cortical tubers. A large proportion of patients with TSC exhibit neurological symptoms including epilepsy and intellectual disability, and a further 50% meet the diagnostic criteria for Autism. However, the appearance of this broad spectrum of neurologic manifestations does not always correlate with the neuroanatomical defects common to TSC, suggesting the possibility of underlying functional defects affecting neural development in TSC patients. Here we have utilized neural progenitor cells (NPCs) capable of fully differentiating into neurons, which carry a heterozygous TSC2 mutation generated from patient-derived induced pluripotent stem cells (iPSCs) to investigate TSC cellular and molecular phenotypes. In these cell lines we observe that TSC2 +/ NPCs exhibit changes in cell signaling along the Akt/mTORC1 signaling axis. This pathway is classically affected in TSC, with elevated pS6 and decreased phospho-Akt levels known as neuropathological hallmarks in knockout mouse models and studies of abnormal human tissue. Consistent with these previous findings we observed a decrease in the activity of AKT as measured by levels of phospho-AKT Thr308 and Ser473. Evidence of increased mTORC1 signaling was seen in one patient, but not another, suggesting TSC2 heterozygosity may produce modest signaling changes near a functional threshold for generating a molecular phenotype in NPCs. TSC2 heterozygous NPCs also exhibited a reduced capacity to produce neurons in vitro, suggesting that neural development may be impacted in TSC. Moreover, this phenotype was reproduced upon AKT inhibition of control NPC lines, but was unaffected under treatment with rapamycin, suggesting that AKT signaling may play a more prominent role in mediating the neurodevelopmental defects of TSC than previously thought.
Subject (authority = RUETD)
Topic
Neuroscience
Subject (authority = ETD-LCSH)
Topic
Tuberous sclerosis
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_9243
PhysicalDescription
Form (authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
1 online resource (140 pages : illustrations)
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
Note (type = statement of responsibility)
by Avery Zucco
RelatedItem (type = host)
TitleInfo
Title
School of Graduate Studies Electronic Theses and Dissertations
Identifier (type = local)
rucore10001600001
Location
PhysicalLocation (authority = marcorg); (displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier (type = doi)
doi:10.7282/t3-9ahy-yx47
Genre (authority = ExL-Esploro)
ETD doctoral
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Rights

RightsDeclaration (ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Zucco
GivenName
Avery
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2018-09-25 15:59:55
AssociatedEntity
Name
Avery Zucco
Role
Copyright holder
Affiliation
Rutgers University. School of Graduate Studies
AssociatedObject
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.
RightsEvent
Type
Embargo
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2018-10-31
DateTime (encoding = w3cdtf); (qualifier = exact); (point = end)
2019-05-02
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after May 2nd, 2019.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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Technical

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ContentModel
ETD
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windows xp
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DateCreated (point = end); (encoding = w3cdtf); (qualifier = exact)
2018-10-02T17:13:30
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1.7
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