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Translational approach to investigat...

Knezevic, Tijana.

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Translational approach to investigate involvement of BAG3 in protein quality control and heart failure.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Translational approach to investigate involvement of BAG3 in protein quality control and heart failure./
作者:	Knezevic, Tijana.
面頁冊數:	69 p.
附註:	Source: Dissertation Abstracts International, Volume: 77-10(E), Section: B.
Contained By:	Dissertation Abstracts International77-10B(E).
標題:	Biology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10111387
ISBN:	9781339745961

Translational approach to investigate involvement of BAG3 in protein quality control and heart failure.
Knezevic, Tijana.

Translational approach to investigate involvement of BAG3 in protein quality control and heart failure. - 69 p.

Source: Dissertation Abstracts International, Volume: 77-10(E), Section: B.

Thesis (Ph.D.)--Temple University, 2016.

Heart failure continues to be a global problem, even with all the drugs currently available, leading to a need of new therapeutics to decrease incidence of heart failure. Heart failure is the inability of the heart muscle to pump sufficient blood and oxygen to the rest of the body. One of the causes of heart failure is cardiomyopathy, where cardiac muscle becomes larger and weaker. Genetic mutations in genes encoding sarcomeric, structural and cytoskeletal proteins were found in families that developed cardiomyopathy. Our laboratory has indentified a family with heart failure in whom a novel mutation in the BCL2-associated athanogene 3 (BAG3) has been characterized. Among other cardiomyopathy-causing BAG3 mutations reported in various laboratories. Several BAG3 mutations in humans are known to cause familial dilated cardiomyopathy, myofibrilar myopathy, and giant axonal neuropathy.

ISBN: 9781339745961Subjects--Topical Terms:

522710
Biology.

Translational approach to investigate involvement of BAG3 in protein quality control and heart failure.
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245 1 0 $a Translational approach to investigate involvement of BAG3 in protein quality control and heart failure.
300 $a 69 p.
500 $a Source: Dissertation Abstracts International, Volume: 77-10(E), Section: B.
500 $a Adviser: Kamel Khalili.
502 $a Thesis (Ph.D.)--Temple University, 2016.
520 $a Heart failure continues to be a global problem, even with all the drugs currently available, leading to a need of new therapeutics to decrease incidence of heart failure. Heart failure is the inability of the heart muscle to pump sufficient blood and oxygen to the rest of the body. One of the causes of heart failure is cardiomyopathy, where cardiac muscle becomes larger and weaker. Genetic mutations in genes encoding sarcomeric, structural and cytoskeletal proteins were found in families that developed cardiomyopathy. Our laboratory has indentified a family with heart failure in whom a novel mutation in the BCL2-associated athanogene 3 (BAG3) has been characterized. Among other cardiomyopathy-causing BAG3 mutations reported in various laboratories. Several BAG3 mutations in humans are known to cause familial dilated cardiomyopathy, myofibrilar myopathy, and giant axonal neuropathy.
520 $a BAG3 is a stress induced co-chaperone protein that interacts with several heat shock proteins and acts as an important regulator of protein quality control. Expression of BAG3 is high in cardiac, skeletal and smooth muscle. BAG3 is localized at the z-disk of cardiomyocytes and was shown to be essential in keeping a normal assembly of z-disk proteins during mechanical stretch. Interaction of BAG3 with actin capping protein CapZbeta1 prevents degradation of CapZbeta1 via proteasome system and maintains the integrity of the z-disk. BAG3 was shown to promote clearance of misfolded proteins, such as filamin C, via autophagy. Not only that BAG3 is able to promote clearance of dysfunctional filamin C, but it was found to enhance synthesis of the new filamin. BAG3 deficient mice develop fulminant myopathy and cardiomyopathy with disorganization of z-disk and die after one month of age.
520 $a Not only that BAG3 is involved in myofibrilar stability in the cardiomyocytes and that patients with BAG3 mutations develop cardiomyopathy, but our lab showed that patients with heart failure have decrease levels of BAG3. Since heart failure patients have decreased levels of BAG3, the therapy where BAG3 levels are restored to normal levels may improve heart function. Here, I show that in mouse model of heart failure after MI left ventricle function is restored after administration of AAV9 BAG3. BAG3 overexpression in mouse heart helped the stability of z-disk proteins after mechanical stress and myocardial infarction. Overexpressed BAG3 localizes to z-disk and is also able to increase autophagy in cardiomyocytes and help with clearance of misfolded proteins.
520 $a Taken together, this study shows that BAG3 is a valid and promising new therapeutic target for heart failure patients. BAG3 overexpression is able to induce autophagy and help the heart cope better with stress. Also, AAV9 vector is robustly expressed in the heart after systemic administration, and is a promising vector for gene delivery in the patient heart.
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