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Elucidation of anti-proliferative an...

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Elucidation of anti-proliferative and pro-apoptotic signaling induced by the immunomodulatory benzodiazepine Bz-423.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Elucidation of anti-proliferative and pro-apoptotic signaling induced by the immunomodulatory benzodiazepine Bz-423./
Author:	Sundberg, Thomas B.
Description:	401 p.
Notes:	Adviser: Gary D. Glick.
Contained By:	Dissertation Abstracts International70-04B.
Subject:	Chemistry, Pharmaceutical. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3354188
ISBN:	9781109118117

Elucidation of anti-proliferative and pro-apoptotic signaling induced by the immunomodulatory benzodiazepine Bz-423.
Sundberg, Thomas B.

Elucidation of anti-proliferative and pro-apoptotic signaling induced by the immunomodulatory benzodiazepine Bz-423. - 401 p.

Adviser: Gary D. Glick.

Thesis (Ph.D.)--University of Michigan, 2009.

Bz-423 is a non-anxiolytic 1,4-benzodiazepine that ameliorates disease in animal models of lupus, arthritis and psoriasis. Concomitant with these therapeutic effects, Bz-423 induces lineage-specific apoptosis of pathogenic lymphocytes or selectively blocks proliferation of psoriatic skin cells. Mechanistic studies in B cells demonstrated that Bz-423 promotes mitochondrial superoxide (O2·-) production, and the magnitude of this response distinguishes between growth arrest and apoptosis. The Bz-423 induced O2·- response results from modulation of the FoF1-ATPase. Bz-423 binds to the oligomycin sensitivity-conferring protein (OSCP) component of the FoF 1-ATPase, which causes the rate of ATP synthesis to slow and forces the mitochondrial respiratory chain into a reduced state that favors overproduction of O2·-.

ISBN: 9781109118117Subjects--Topical Terms:

550957
Chemistry, Pharmaceutical.

Elucidation of anti-proliferative and pro-apoptotic signaling induced by the immunomodulatory benzodiazepine Bz-423.
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035 $a (UMI)AAI3354188
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100 1 $a Sundberg, Thomas B. $3 1064710
245 1 0 $a Elucidation of anti-proliferative and pro-apoptotic signaling induced by the immunomodulatory benzodiazepine Bz-423.
300 $a 401 p.
500 $a Adviser: Gary D. Glick.
500 $a Source: Dissertation Abstracts International, Volume: 70-04, Section: B, page: 2316.
502 $a Thesis (Ph.D.)--University of Michigan, 2009.
520 $a Bz-423 is a non-anxiolytic 1,4-benzodiazepine that ameliorates disease in animal models of lupus, arthritis and psoriasis. Concomitant with these therapeutic effects, Bz-423 induces lineage-specific apoptosis of pathogenic lymphocytes or selectively blocks proliferation of psoriatic skin cells. Mechanistic studies in B cells demonstrated that Bz-423 promotes mitochondrial superoxide (O2·-) production, and the magnitude of this response distinguishes between growth arrest and apoptosis. The Bz-423 induced O2·- response results from modulation of the FoF1-ATPase. Bz-423 binds to the oligomycin sensitivity-conferring protein (OSCP) component of the FoF 1-ATPase, which causes the rate of ATP synthesis to slow and forces the mitochondrial respiratory chain into a reduced state that favors overproduction of O2·-.
520 $a The overarching goal of the experiments described in this dissertation is, therefore, to identify factors underlying the selective effects of Bz-423 on pathogenic cells in vivo by elucidating signaling pathways that link elevated mitochondrial O2·- production to growth arrest or apoptosis. Towards this goal, proteasomal degradation of c-Myc, an oncogenic transcription factor that regulates cell-cycle progression, was identified as an essential component of the mechanism leading to Bz-423 induced growth arrest. While this mechanism was identified in B cells, it likely contributes to the anti-psoriatic activity because c-Myc levels are reduced in psoriatic skin treated with Bz-423.
520 $a Although Bz-423 specifically depletes pathogenic CD4+ T cells in the MRL/MpJ-Faslpr murine model of lupus, the apoptotic response to Bz-423 has been characterized primarily in B cells. To address this point, Bz-423-induced apoptosis was investigated in CD4+ T cell leukemia lines. Unlike some pro-oxidants, Bz-423 induced O2 ·- does not cause opening of the mitochondrial permeability transition pore, but instead triggers a specific, extra-mitochondrial cascade marked by increased levels of the pro-apoptototic Bcl-2 family proteins Noxa and Bak. The resulting activation of Bak, commits a cell to die in response to Bz-423 by inducing release of apoptogenic proteins (e.g., cytochrome c) sequestered inside mitochondria. Intersection of this apoptotic mechanism with vulnerabilities in autoreactive T cells, including mitochondrial bioenergetic abnormalities favoring overproduction O2·- and upregulation of Noxa in response to antigenic stimulation, likely underlies the selective depletion of pathogenic lymphocytes in vivo .
590 $a School code: 0127.
650 4 $a Chemistry, Pharmaceutical. $3 550957
650 4 $a Health Sciences, Immunology. $3 1017716
650 4 $a Health Sciences, Pharmacology. $3 1017717
690 $a 0419
690 $a 0491
690 $a 0982
710 2 $a University of Michigan. $3 777416
773 0 $t Dissertation Abstracts International $g 70-04B.
790 $a 0127
790 1 0 $a Glick, Gary D., $e advisor
791 $a Ph.D.
792 $a 2009
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3354188