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Targeting the PI3K/Akt/mTOR pathway in traumatic brain injury and developmental disease
Descriptive
TitleInfo
Title
Targeting the PI3K/Akt/mTOR pathway in traumatic brain injury and developmental disease
Name
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Nikolaeva
NamePart
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Ina
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Ina Nikolaeva
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author
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D'Arcangelo
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Gabriella
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Gabriella D'Arcangelo
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Advisory Committee
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chair
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(type = personal)
NamePart
(type = family)
Firestein
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(type = given)
Bonnie L
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Bonnie L Firestein
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Advisory Committee
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internal member
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(type = personal)
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(type = family)
Xie
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(type = given)
Ping
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Ping Xie
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Advisory Committee
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(authority = RULIB)
internal member
Name
(type = personal)
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(type = family)
Alder
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(type = given)
Janet
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Janet Alder
Affiliation
Advisory Committee
Role
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(authority = RULIB)
outside member
Name
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NamePart
Rutgers University
Role
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(authority = RULIB)
degree grantor
Name
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NamePart
Graduate School - New Brunswick
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school
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Text
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theses
OriginInfo
DateCreated
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2016
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2016-05
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2016
Place
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xx
Language
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eng
Abstract
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The PI3K/Akt/mTOR signaling pathway mediates many aspects of cell growth and regeneration. Dysregulation of the pathway during development or following injury can lead to severe symptoms, including behavioral disorders, intellectual disability and seizures. We investigated the effects of excess PI3K/Akt/mTOR signaling in the mouse brain during embryonic development and following traumatic brain injury; we then tested out known inhibitors of the pathway for their potential to prevent or reverse the resulting damage. Here, we described the time course and cell specificity of mTORC1 signal activation in the mouse hippocampus after moderate controlled cortical impact (CCI), and identified an early neuronal peak of activity that occurs within few hours after injury. We suppressed this peak activity by a single injection of the mTORC1 inhibitor rapamycin one hour after CCI, and showed that this acute treatment significantly diminishes the extent of neuronal death and astrogliosis within 24 hours after injury. We investigated two other suppressor compounds of the pathway, mTORC1 inhibitor RAD001 and Akt inhibitor MK-2206, in an in vitro mouse model of excess developmental PI3K/Akt/mTOR activity; increased signaling in this pathway is associated with multiple brain overgrowth disorders in humans. We used excitatory neuron-specific gene deletion of the PI3K antagonist Pten as a method for disinhibiting the pathway. We established Pten-mutant forebrain neuronal cultures as an in vitro model of brain overgrowth that may facilitate the identification of pharmacological treatments. We found that Pten-mutant neurons exhibit dramatic cellular hypertrophy, including increased soma size and dendrite complexity, which can be reversed partially with mTORC1 inhibitor RAD001 and fully with Akt inhibitor MK-2206. Our findings suggest that acute Akt and mTORC1 inhibition may offer viable therapeutic approaches for preventing or reversing pathologies caused by excess PI3K/Akt/mTOR signaling, both in the developing and healing brain.
Subject
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Topic
Microbiology and Molecular Genetics
Subject
(authority = ETD-LCSH)
Topic
Biology, Molecular
Subject
(authority = ETD-LCSH)
Topic
Barin--Wounds and injuries
RelatedItem
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Title
Rutgers University Electronic Theses and Dissertations
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ETD_7055
PhysicalDescription
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electronic resource
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application/pdf
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text/xml
Extent
1 online resource (ix, 104 p. : ill.)
Note
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Ph.D.
Note
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Includes bibliographical references
Note
(type = statement of responsibility)
by Ina Nikolaeva
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TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
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rucore19991600001
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NjNbRU
Identifier
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doi:10.7282/T3CZ39BH
Genre
(authority = ExL-Esploro)
ETD doctoral
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Rights
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The author owns the copyright to this work.
RightsHolder
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Name
FamilyName
Nikolaeva
GivenName
Ina
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime
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2016-03-06 15:41:57
AssociatedEntity
Name
Ina Nikolaeva
Role
Copyright holder
Affiliation
Rutgers University. Graduate School - New Brunswick
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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
DateTime
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2016-05-31
DateTime
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2018-05-31
Type
Embargo
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after May 31st, 2018.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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windows xp
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