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Autophagy in tissue homeostasis and cancer

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TitleInfo
Title
Autophagy in tissue homeostasis and cancer
Name (type = personal)
NamePart (type = family)
Karsli Uzunbas
NamePart (type = given)
Gizem
NamePart (type = date)
1984-
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Gizem Karsli Uzunbas
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
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White
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Eileen
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Eileen White
Affiliation
Advisory Committee
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chair
Name (type = personal)
NamePart (type = family)
JIN
NamePart (type = given)
SHENGKAN (VICTOR)
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SHENGKAN (VICTOR) JIN
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Advisory Committee
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internal member
Name (type = personal)
NamePart (type = family)
Karantza
NamePart (type = given)
Vassiliki
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Vassiliki Karantza
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Advisory Committee
Role
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internal member
Name (type = personal)
NamePart (type = family)
RABINOWITZ
NamePart (type = given)
JOSHUA
DisplayForm
JOSHUA RABINOWITZ
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
outside member
Name (type = personal)
NamePart (type = family)
Xia
NamePart (type = given)
Bing
DisplayForm
Bing Xia
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
Graduate School - New Brunswick
Role
RoleTerm (authority = RULIB)
school
TypeOfResource
Text
Genre (authority = marcgt)
theses
Genre (authority = ExL-Esploro)
ETD doctoral
OriginInfo
DateCreated (encoding = w3cdtf); (qualifier = exact)
2015
DateOther (qualifier = exact); (type = degree)
2015-01
CopyrightDate (encoding = w3cdtf); (qualifier = exact)
2015
Place
PlaceTerm (type = code)
xx
Language
LanguageTerm (authority = ISO639-2b); (type = code)
eng
Abstract (type = abstract)
Macroautophagy (autophagy hereafter) is a protective process that recycles cellular components to maintain homeostasis and survival. By removing damaged protein and organelles, autophagy ensures protein and organelle quality control. In cancer, the role of autophagy is context dependent. Autophagy is an essential survival mechanism during starvation that promotes tumor progression, but there are also cases where autophagy can suppress tumorigenesis in mouse models. Thus, understanding the role of autophagy modulation in cancer is critical for cancer therapy. Tumors with RAS mutations require autophagy to tolerate metabolic stress, suggesting that autophagy inhibition may be a potential approach in cancer therapy. However, how systemic autophagy inactivation differentially affects normal and tumor tissues is unknown. To assess the functional significance of autophagy, we conditionally deleted the essential autophagy gene, Atg7, throughout adult mice. In that way, we could model the consequences of autophagy inactivation simultaneously to both normal and tumor tissue to simulate autophagy inhibition in cancer therapy. First, we wanted to identify what happens to an adult mouse when autophagy is turned off. We generated a mouse model to delete Atg7, throughout the entire mouse to determine the role of autophagy in adult mammal. Systemic ATG7 ablation caused susceptibility to infection and neurodegeneration that limited survival to 2-3 months. Moreover, autophagy was required to maintain fat stores and to mobilize free fatty acids specifically in response to fasting. Also, upon fasting, autophagy-deficient mice suffered muscle wasting and fatal hypoglycemia that is mediated by p53. Not only limited to the starvation stress response, inhibiting autophagy also increased sensitivity to γ-irradiation-induced death. Second, knowing that there is a window of time that adult mice can survive without autophagy, we examined if autophagy ablation is selectively toxic to tumors while sparing normal tissues. For this purpose, we generated another mouse model to induce non-small-cell lung cancer (NSCLC) and then prior to or once tumors were established, we acutely ablated autophagy. Prior autophagy ablation did not alter the efficiency of NSCLC initiation by activation of oncogenic KrasG12D and deletion of the Trp53 tumor suppressor. Acute autophagy ablation in mice with pre-existing NSCLC, however, blocked tumor growth, promoted tumor cell death, and generated more benign cancer with oncocytic changes. Moreover, host autophagy contributed to tumor growth. This anti-tumor activity occurred prior to destruction of normal tissues, suggesting that, acute autophagy inhibition may be therapeutically beneficial in cancer.
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
ETD_6051
Identifier (type = doi)
doi:10.7282/T31J9CHM
PhysicalDescription
Form (authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
1 online resource (xviii, 108 p. : ill.)
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references
Note (type = statement of responsibility)
by Gizem Karsli Uzunbas
Subject (authority = ETD-LCSH)
Topic
Homeostasis
Subject (authority = ETD-LCSH)
Topic
Tumors
Subject (authority = ETD-LCSH)
Topic
Cancer--Treatment
Location
PhysicalLocation (authority = marcorg); (displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Subject (authority = RUETD)
Topic
Biochemistry
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Rights

RightsDeclaration (ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Karsli Uzunbas
GivenName
Gizem
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2014-12-11 12:22:57
AssociatedEntity
Name
GIZEM KARSLI UZUNBAS
Role
Copyright holder
Affiliation
Rutgers University. Graduate School - New Brunswick
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
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2015-01-31
DateTime (encoding = w3cdtf); (qualifier = exact); (point = end)
2016-01-31
Type
Embargo
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after January 31st, 2016.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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Technical

RULTechMD (ID = TECHNICAL1)
ContentModel
ETD
OperatingSystem (VERSION = 5.1)
windows xp
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