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Using LNS8801, a GPER agonist, to treat GRM1+ melanoma in a transgenic mouse model
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TitleInfo
Title
Using LNS8801, a GPER agonist, to treat GRM1+ melanoma in a transgenic mouse model
Name
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Marinaro
NamePart
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Christina N.
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1995-
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Christina N. Marinaro
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(authority = RULIB)
author
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Audrey
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Audrey Minden
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Advisory Committee
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chair
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Rutgers University
Role
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(authority = RULIB)
degree grantor
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School of Graduate Studies
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school
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Text
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theses
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ETD graduate
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2020
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2020-10
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2020
Language
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(authority = ISO 639-3:2007);
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English
Abstract
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Melanoma is the most aggressive form of skin cancer. The American Cancer Society estimated that over 100,000 new cases will be diagnosed and there will be over 7,000 deaths from the disease in 2020. There are several signaling pathways critical for the onset and progression of this deadly disease. The sex hormone, estrogen, has been shown to act directly on melanocytes through G-protein coupled estrogen receptors (GPER). This interaction results in increased pigmentation and differentiation in melanocytes to establish a protective effect against cellular transformation. The activation and subsequent signaling cascades associated with GPER are unique to melanocytes and do not overlap with the classical estrogen pathways. Linnaeus Therapeutics Inc. has identified and isolated a unique isomer, LNS8801 as the active component of the GPER agonist G-1. Previous studies with LNS8801 in melanoma allograft mouse models showed a reduction in tumor progression and a lasting protective activity upon secondary challenge of the same tumor cells.
Our lab was the first to show that ectopic expression of a normal neuronal receptor, metabotropic glutamate receptor 1 (mGluR1/GRM1) in melanocytes is sufficient to transform cells in vitro and induce tumors in vivo. We established two transgenic mouse models, TG-3 and TGS, with aberrant GRM1 expression that develop metastatic melanoma spontaneously with 100% penetrance. In this project we propose to use the unique TGS mouse model and treat the animals with LNS8801 over 32 weeks to see the consequences of activated GPER. Furthermore, to emulate exposure to the natural carcinogen, UV radiation, most people endure every day, we will expose mice to UV throughout the study. Possible alterations in disease progression will be monitored by a small animal imaging system (IVIS). Several key protein markers shown earlier to be involved in GPER signaling will be evaluated by Western blots in excised tumor tissue samples. Finally, cytokine analysis will also be performed to examine possible changes in levels of cytokines, two specific ones, interlukin-10 (IL-10) and interferon gamma (IFN-γ), shown in previous investigations.
Our lab was the first to show that ectopic expression of a normal neuronal receptor, metabotropic glutamate receptor 1 (mGluR1/GRM1) in melanocytes is sufficient to transform cells in vitro and induce tumors in vivo. We established two transgenic mouse models, TG-3 and TGS, with aberrant GRM1 expression that develop metastatic melanoma spontaneously with 100% penetrance. In this project we propose to use the unique TGS mouse model and treat the animals with LNS8801 over 32 weeks to see the consequences of activated GPER. Furthermore, to emulate exposure to the natural carcinogen, UV radiation, most people endure every day, we will expose mice to UV throughout the study. Possible alterations in disease progression will be monitored by a small animal imaging system (IVIS). Several key protein markers shown earlier to be involved in GPER signaling will be evaluated by Western blots in excised tumor tissue samples. Finally, cytokine analysis will also be performed to examine possible changes in levels of cytokines, two specific ones, interlukin-10 (IL-10) and interferon gamma (IFN-γ), shown in previous investigations.
Subject
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Topic
Cancer
Subject
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Topic
Microbiology and Molecular Genetics
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Rutgers University Electronic Theses and Dissertations
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ETD_11188
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application/pdf
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1 online resource (viii, 63 pages) : illustrations
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M.S.
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Includes bibliographical references
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School of Graduate Studies Electronic Theses and Dissertations
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rucore10001600001
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NjNbRU
Identifier
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doi:10.7282/t3-gyrr-hs11
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Rights
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The author owns the copyright to this work.
RightsHolder
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Name
FamilyName
Marinaro
GivenName
Christina
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Copyright Holder
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Permission or license
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2020-09-23 09:15:33
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Name
Christina Marinaro
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Copyright holder
Affiliation
Rutgers University. School of Graduate Studies
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Author Agreement License
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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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Embargo
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2020-10-31
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2022-10-31
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after October 31st, 2022.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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windows xp
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2020-09-21T13:11:32
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2020-09-21T13:11:32
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