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UDP-glucose glycoprotein glucosyltransferase (uggt-1) and UPR genes modulate C. elegans necrotic cell death

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TypeOfResource
Text
TitleInfo (ID = T-1)
Title
UDP-glucose glycoprotein glucosyltransferase (uggt-1) and UPR genes modulate C. elegans necrotic cell death
SubTitle
PartName
PartNumber
NonSort
Identifier (displayLabel = ); (invalid = )
ETD_2052
Identifier (type = hdl)
http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.000051886
Language (objectPart = )
LanguageTerm (authority = ISO639-2); (type = code)
eng
Genre (authority = marcgt)
theses
Subject (ID = SBJ-1); (authority = RUETD)
Topic
Cell and Developmental Biology
Subject (ID = SBJ-2); (authority = ETD-LCSH)
Topic
Caenorhabditis elegans--Genetics
Subject (ID = SBJ-3); (authority = ETD-LCSH)
Topic
Cell death
Abstract
Contrary to an initial understanding of necrosis as a chaotic, non-regulated type of cell death, recent studies suggest that necrotic cell death (NCD) is a consequence of a complex and lethal cascade of genetically-encoded events. Necrosis underlies the pathology of many neurodegenerative diseases, stroke, and traumatic injury. In the Driscoll Lab, NCD mechanisms have been addressed for several years taking advantage of unique genetic and molecular biology tools developed in the model organism Caenorhabditis elegans. The necrotic paradigm we study the most involves initiation of cell death by hyperactivated ion channels expressed in six touch-sensory neurons and requires elevation of intracellular Ca2+, which activates calpain and cathepsin proteases.
I exploited the unique features of our model system to uncover novel genetic factors influencing this process. To this end, I conducted a high-throughput forward genetic screen to identify mutations that block or delay necrotic cell death induced by MEC-4(d) channel hyperactivation, and genetically mapped novel mutations capable of blocking or slowing the death process. I exploited an automated mutational screening capacity that allows sorting of individual animals based on detection of fluorescent signals that, in our particular case, had been engineered to indicate neuronal viability. I focused on the cloning of two novel mutant loci and dissected molecular mechanisms responsible for death suppression. In addition, I studied the impact of a major subset of calcium homeostasis genes in a C. elegans model of Aβ toxicity.
My research adds a new component to the current understanding of NCD, suggesting that inability to cope with endoplasmic reticulum stress (presumably induced by calcium depletion inside the ER, which affects chaperone functionality) plays an important role in progression through necrosis. I discovered that mild activation of an intact unfolded protein response (UPR), e.g., as induced by downregulation of UDP-glucose:glycoprotein glucosyltransferase (UGGT, an ER-resident enzyme involved in high-fidelity protein folding quality control) or mild increments in ambient temperature, can partially suppress necrosis in our C. elegans model, reminiscent of beneficial preconditioning effects in mammals. Additionally I found that several UPR transducers contribute to such modulation of cell death in a “tug-of-war” fashion. Our refined model of molecular mechanisms contributing and modulating necrosis suggests new strategies that could eventually limit the devastating effects of necrosis in human injury and disease.
PhysicalDescription
Form (authority = gmd)
electronic resource
Extent
xvi, 175 p. : ill.
InternetMediaType
application/pdf
InternetMediaType
text/xml
Note
Supplementary File: Authorizing Communications from other Authors
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references (p. 154-174)
Note (type = statement of responsibility)
by Yury Orlando Nunez Lopez
Name (ID = NAME-1); (type = personal)
NamePart (type = family)
Nunez Lopez
NamePart (type = given)
Yury Orlando
NamePart (type = date)
1971-
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author
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Yury Orlando Nunez Lopez
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Padgett
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Richard
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chair
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Advisory Committee
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Richard Padgett
Name (ID = NAME-3); (type = personal)
NamePart (type = family)
Konsolaki
NamePart (type = given)
Mary
Role
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co-chair
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Advisory Committee
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Mary Konsolaki
Name (ID = NAME-4); (type = personal)
NamePart (type = family)
Driscoll
NamePart (type = given)
Monica
Role
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internal member
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Advisory Committee
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Monica Driscoll
Name (ID = NAME-5); (type = personal)
NamePart (type = family)
Wadsworth
NamePart (type = given)
William
Role
RoleTerm (authority = RULIB); (type = )
outside member
Affiliation
Advisory Committee
DisplayForm
William Wadsworth
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)
2009-10
Place
PlaceTerm (type = code)
xx
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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
Location
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NjNbRU
Identifier (type = doi)
doi:10.7282/T3M61KDJ
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
Notice
Note
Availability
Status
Open
Reason
Permission or license
Note
RightsHolder (ID = PRH-1); (type = personal)
Name
FamilyName
Nunez Lopez
GivenName
Yury
Role
Copyright holder
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Type
Permission or license
Label
Place
DateTime
Detail
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Copyright holder
Name
Yury Nunez Lopez
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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