東華大學圖書館 |

語系: 繁體中文

說明(常見問題)

回圖書館首頁

手機版館藏查詢

登入

回首頁

切換: 標籤 | MARC模式 | ISBD

Data-Driven Analysis of Phospho-Sign...

Fong, Linda Ellen.

FindBook

Google Book

Amazon

博客來

Data-Driven Analysis of Phospho-Signaling Network Responses Enables Latent HIV Infected T Cell Targeting.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Data-Driven Analysis of Phospho-Signaling Network Responses Enables Latent HIV Infected T Cell Targeting./
作者:	Fong, Linda Ellen.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
面頁冊數:	213 p.
附註:	Source: Dissertations Abstracts International, Volume: 80-02, Section: B.
Contained By:	Dissertations Abstracts International80-02B.
標題:	Caribbean Studies. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10957324
ISBN:	9780438273696

Data-Driven Analysis of Phospho-Signaling Network Responses Enables Latent HIV Infected T Cell Targeting.
Fong, Linda Ellen.

Data-Driven Analysis of Phospho-Signaling Network Responses Enables Latent HIV Infected T Cell Targeting. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 213 p.

Source: Dissertations Abstracts International, Volume: 80-02, Section: B.

Thesis (Ph.D.)--Yale University, 2018.

This item must not be added to any third party search indexes.

Viral latency remains the most significant obstacle to HIV eradication. Current clinical strategies aim to purge the latent CD4+ T cell reservoir by activating viral expression, but are undercut by the inability to clear the latent reservoir. We first evaluated co-drugging criteria in a quantitative manner to optimize viral expression. However, this approach faces many challenges; and thus, we proposed to identify and target dysregulated signaling pathways in latent HIV-infected cells to promote cell death as a novel approach for eradication. To identify how HIV latency and reactivation alter signal transduction pathways regulating cell death, we explored the acute signaling response of latent HIV-infected CD4+ T cells across in vitro human latency models using systems-level analyses. We measured phosphorylation of five signaling proteins (AKT, IKBa, ERK, p38, and JNK) after stimulation with T-cell activating agents or latency reversing agents in infected cells and uninfected cells. Using these phosphorylation signatures, we built data-driven statistical models that successfully classified infected and uninfected cells, demonstrating that latent infection alters signaling at a systems level. We further identified that the stress kinase pathways p38 and JNK exhibited elevated signaling in latently infected cells and could be targeted to specifically increase cell death, independent of HIV reactivation. To work out the mechanisms by which latent and reactivating HIV alters cell death regulation, we further examined signaling of 31 proteins in single cells over 48 hours using mass cytometry. Mass cytometry provides measurements at single-cell resolution, enabling us to separate responses in cells with latent versus reactivating HIV based on viral expression. We used conditional density-based analysis of the single-cell data to quantify the strength of signaling activity along different pathways. We discovered that latent and HIV-expressing cells are sensitized to apoptotic cell death via activation of p38-p53 signaling and inhibition of AKT/mTOR signaling. We identified a novel interaction in infected cells, in which increased p38 signaling activates the pro-death activity of the protein BAD, leading to increased apoptosis. Finally, we show in vitro that p38 and AKT/mTOR pathways can be simultaneously targeted to deplete the latent reservoir by preferentially killing latently infected cells without viral activation. Overall, we demonstrate that targeting altered phosphorylation signatures of latent HIV-infected cells provides a novel and effective strategy for latent HIV eradication.

ISBN: 9780438273696Subjects--Topical Terms:

1670141
Caribbean Studies.

Data-Driven Analysis of Phospho-Signaling Network Responses Enables Latent HIV Infected T Cell Targeting.
LDR:03813nmm a2200349 4500 001 2197563
005 20190923134345.5
008 200811s2018 ||||||||||||||||| ||eng d
020 $a 9780438273696
035 $a (MiAaPQ)AAI10957324
035 $a AAI10957324
035 $a 2197563
040 $a MiAaPQ $c MiAaPQ
100 1 $a Fong, Linda Ellen. $3 3422386
245 1 0 $a Data-Driven Analysis of Phospho-Signaling Network Responses Enables Latent HIV Infected T Cell Targeting.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2018
300 $a 213 p.
500 $a Source: Dissertations Abstracts International, Volume: 80-02, Section: B.
500 $a Publisher info.: Dissertation/Thesis.
500 $a Advisor: Miller-Jensen, Kathryn.
502 $a Thesis (Ph.D.)--Yale University, 2018.
506 $a This item must not be added to any third party search indexes.
506 $a This item must not be sold to any third party vendors.
520 $a Viral latency remains the most significant obstacle to HIV eradication. Current clinical strategies aim to purge the latent CD4+ T cell reservoir by activating viral expression, but are undercut by the inability to clear the latent reservoir. We first evaluated co-drugging criteria in a quantitative manner to optimize viral expression. However, this approach faces many challenges; and thus, we proposed to identify and target dysregulated signaling pathways in latent HIV-infected cells to promote cell death as a novel approach for eradication. To identify how HIV latency and reactivation alter signal transduction pathways regulating cell death, we explored the acute signaling response of latent HIV-infected CD4+ T cells across in vitro human latency models using systems-level analyses. We measured phosphorylation of five signaling proteins (AKT, IKBa, ERK, p38, and JNK) after stimulation with T-cell activating agents or latency reversing agents in infected cells and uninfected cells. Using these phosphorylation signatures, we built data-driven statistical models that successfully classified infected and uninfected cells, demonstrating that latent infection alters signaling at a systems level. We further identified that the stress kinase pathways p38 and JNK exhibited elevated signaling in latently infected cells and could be targeted to specifically increase cell death, independent of HIV reactivation. To work out the mechanisms by which latent and reactivating HIV alters cell death regulation, we further examined signaling of 31 proteins in single cells over 48 hours using mass cytometry. Mass cytometry provides measurements at single-cell resolution, enabling us to separate responses in cells with latent versus reactivating HIV based on viral expression. We used conditional density-based analysis of the single-cell data to quantify the strength of signaling activity along different pathways. We discovered that latent and HIV-expressing cells are sensitized to apoptotic cell death via activation of p38-p53 signaling and inhibition of AKT/mTOR signaling. We identified a novel interaction in infected cells, in which increased p38 signaling activates the pro-death activity of the protein BAD, leading to increased apoptosis. Finally, we show in vitro that p38 and AKT/mTOR pathways can be simultaneously targeted to deplete the latent reservoir by preferentially killing latently infected cells without viral activation. Overall, we demonstrate that targeting altered phosphorylation signatures of latent HIV-infected cells provides a novel and effective strategy for latent HIV eradication.
590 $a School code: 0265.
650 4 $a Caribbean Studies. $3 1670141
650 4 $a Biomedical engineering. $3 535387
650 4 $a Immunology. $3 611031
690 $a 0432
690 $a 0541
690 $a 0982
710 2 $a Yale University. $3 515640
773 0 $t Dissertations Abstracts International $g 80-02B.
790 $a 0265
791 $a Ph.D.
792 $a 2018
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10957324