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

FindBook

Google Book

Amazon

博客來

The Role of Proteotoxicity and Cross-Organelle Stress Response in Drug-Induced Acute Kidney Injury.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	The Role of Proteotoxicity and Cross-Organelle Stress Response in Drug-Induced Acute Kidney Injury./
作者:	Igwebuike, Chinaemere.
面頁冊數:	1 online resource (226 pages)
附註:	Source: Dissertations Abstracts International, Volume: 81-12, Section: B.
Contained By:	Dissertations Abstracts International81-12B.
標題:	Molecular biology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=27829505click for full text (PQDT)
ISBN:	9798645468804

The Role of Proteotoxicity and Cross-Organelle Stress Response in Drug-Induced Acute Kidney Injury.
Igwebuike, Chinaemere.

The Role of Proteotoxicity and Cross-Organelle Stress Response in Drug-Induced Acute Kidney Injury. - 1 online resource (226 pages)

Source: Dissertations Abstracts International, Volume: 81-12, Section: B.

Thesis (Ph.D.)--Boston University, 2022.

Includes bibliographical references

Nephrotoxicity is a dose-limiting side effect of gentamicin that accounts for a significant portion of clinical acute kidney injury (AKI). The mechanism of gentamicin-induced nephrotoxicity is uncertain and effective therapy for gentamicin-induced renal cell injury is limited by incomplete mechanistic insight. To address this challenge, we hypothesized that RNAi signal pathway screening can identify both a unifying mechanism of gentamicin-induced cell injury and a therapeutic that ameliorates its toxicity. Dual shRNA screens of 5,000 individually barcoded signal pathway genes were performed in gentamicin-exposed human proximal tubule cell lines and differentially expressed shRNAs were analyzed by Ingenuity Pathways Analysis (IPA) software. Computational analysis of RNAi signal screens identified the Cross-Organelle Stress Response (CORE), the Unfolded Protein Response (UPR), and cell chaperones as key injury targets of gentamicin-induced proteotoxicity. To validate these injury mechanisms, we assessed the effect of gentamicin on the CORE, UPR and cell chaperone function, and tested the therapeutic efficacy of enhancing cell chaperone content. Early gentamicin exposure disrupted the CORE, evidenced by a rise in the ATP:ADP ratio, mitochondrial-specific H2O2 accumulation, Drp-1 associated mitochondrial fragmentation, and endoplasmic reticulum-mitochondrial dissociation. CORE disruption preceded measurable increases in whole cell oxidative stress, misfolded protein content, transcriptional UPR activation and its untoward downstream effects: CHOP expression, PARP cleavage and cell death. Geranylgeranylacetone, a therapeutic that increases cell chaperone content, prevented mitochondrial H2O2 accumulation, preserved the CORE, reduced the burden of misfolded proteins and CHOP expression, and significantly improved survival in gentamicin-exposed cells. We identify CORE disruption as an early and remediable cause of gentamicin proteotoxicity that precedes downstream cytosolic UPR activation and cell death. Preserving the CORE is associated with improved renal cell survival likely by reducing organelle-specific proteotoxicity during gentamicin exposure.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9798645468804Subjects--Topical Terms:

517296
Molecular biology.
Subjects--Index Terms:

Acute kidney injuryIndex Terms--Genre/Form:

542853
Electronic books.

The Role of Proteotoxicity and Cross-Organelle Stress Response in Drug-Induced Acute Kidney Injury.
LDR:03594nmm a2200409K 4500 001 2359306
005 20230917193906.5
006 m o d
007 cr mn ---uuuuu
008 241011s2022 xx obm 000 0 eng d
020 $a 9798645468804
035 $a (MiAaPQ)AAI27829505
035 $a AAI27829505
040 $a MiAaPQ $b eng $c MiAaPQ $d NTU
100 1 $a Igwebuike, Chinaemere. $3 3699900
245 1 4 $a The Role of Proteotoxicity and Cross-Organelle Stress Response in Drug-Induced Acute Kidney Injury.
264 0 $c 2022
300 $a 1 online resource (226 pages)
336 $a text $b txt $2 rdacontent
337 $a computer $b c $2 rdamedia
338 $a online resource $b cr $2 rdacarrier
500 $a Source: Dissertations Abstracts International, Volume: 81-12, Section: B.
500 $a Advisor: Borkan, Steven C.
502 $a Thesis (Ph.D.)--Boston University, 2022.
504 $a Includes bibliographical references
520 $a Nephrotoxicity is a dose-limiting side effect of gentamicin that accounts for a significant portion of clinical acute kidney injury (AKI). The mechanism of gentamicin-induced nephrotoxicity is uncertain and effective therapy for gentamicin-induced renal cell injury is limited by incomplete mechanistic insight. To address this challenge, we hypothesized that RNAi signal pathway screening can identify both a unifying mechanism of gentamicin-induced cell injury and a therapeutic that ameliorates its toxicity. Dual shRNA screens of 5,000 individually barcoded signal pathway genes were performed in gentamicin-exposed human proximal tubule cell lines and differentially expressed shRNAs were analyzed by Ingenuity Pathways Analysis (IPA) software. Computational analysis of RNAi signal screens identified the Cross-Organelle Stress Response (CORE), the Unfolded Protein Response (UPR), and cell chaperones as key injury targets of gentamicin-induced proteotoxicity. To validate these injury mechanisms, we assessed the effect of gentamicin on the CORE, UPR and cell chaperone function, and tested the therapeutic efficacy of enhancing cell chaperone content. Early gentamicin exposure disrupted the CORE, evidenced by a rise in the ATP:ADP ratio, mitochondrial-specific H2O2 accumulation, Drp-1 associated mitochondrial fragmentation, and endoplasmic reticulum-mitochondrial dissociation. CORE disruption preceded measurable increases in whole cell oxidative stress, misfolded protein content, transcriptional UPR activation and its untoward downstream effects: CHOP expression, PARP cleavage and cell death. Geranylgeranylacetone, a therapeutic that increases cell chaperone content, prevented mitochondrial H2O2 accumulation, preserved the CORE, reduced the burden of misfolded proteins and CHOP expression, and significantly improved survival in gentamicin-exposed cells. We identify CORE disruption as an early and remediable cause of gentamicin proteotoxicity that precedes downstream cytosolic UPR activation and cell death. Preserving the CORE is associated with improved renal cell survival likely by reducing organelle-specific proteotoxicity during gentamicin exposure.
533 $a Electronic reproduction. $b Ann Arbor, Mich. : $c ProQuest, $d 2023
538 $a Mode of access: World Wide Web
650 4 $a Molecular biology. $3 517296
650 4 $a Medicine. $3 641104
650 4 $a Therapy. $3 3343697
653 $a Acute kidney injury
653 $a Genetic screening
653 $a Gentamicin
653 $a Mitochondria
653 $a Nephrology
653 $a Nephrotoxicity
655 7 $a Electronic books. $2 lcsh $3 542853
690 $a 0307
690 $a 0564
690 $a 0212
710 2 $a ProQuest Information and Learning Co. $3 783688
710 2 $a Boston University. $b Molecular and Translational Medicine GMS. $3 3285971
773 0 $t Dissertations Abstracts International $g 81-12B.
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=27829505 $z click for full text (PQDT)