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You searched for +publisher:"Temple University" +contributor:("Feldman, Arthur M."). Showing records 1 – 2 of 2 total matches.

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Temple University

1. Knezevic, Tijana. TRANSLATIONAL APPROACH TO INVESTIGATE INVOLVEMENT OF BAG3 IN PROTEIN QUALITY CONTROL AND HEART FAILURE.

Degree: PhD, 2016, Temple University

Biology

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. 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. 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. 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.

Temple University – Theses

Advisors/Committee Members: Khalili, Kamel;, Amini, Shohreh, Giordano, Antonio, MD, Feldman, Arthur M. (Arthur Michael);.

Subjects/Keywords: Biology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Knezevic, T. (2016). TRANSLATIONAL APPROACH TO INVESTIGATE INVOLVEMENT OF BAG3 IN PROTEIN QUALITY CONTROL AND HEART FAILURE. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,374885

Chicago Manual of Style (16th Edition):

Knezevic, Tijana. “TRANSLATIONAL APPROACH TO INVESTIGATE INVOLVEMENT OF BAG3 IN PROTEIN QUALITY CONTROL AND HEART FAILURE.” 2016. Doctoral Dissertation, Temple University. Accessed July 02, 2020. http://digital.library.temple.edu/u?/p245801coll10,374885.

MLA Handbook (7th Edition):

Knezevic, Tijana. “TRANSLATIONAL APPROACH TO INVESTIGATE INVOLVEMENT OF BAG3 IN PROTEIN QUALITY CONTROL AND HEART FAILURE.” 2016. Web. 02 Jul 2020.

Vancouver:

Knezevic T. TRANSLATIONAL APPROACH TO INVESTIGATE INVOLVEMENT OF BAG3 IN PROTEIN QUALITY CONTROL AND HEART FAILURE. [Internet] [Doctoral dissertation]. Temple University; 2016. [cited 2020 Jul 02]. Available from: http://digital.library.temple.edu/u?/p245801coll10,374885.

Council of Science Editors:

Knezevic T. TRANSLATIONAL APPROACH TO INVESTIGATE INVOLVEMENT OF BAG3 IN PROTEIN QUALITY CONTROL AND HEART FAILURE. [Doctoral Dissertation]. Temple University; 2016. Available from: http://digital.library.temple.edu/u?/p245801coll10,374885


Temple University

2. Myers, Valerie. The Role of BAG3 in the Failing Heart.

Degree: PhD, 2018, Temple University

Biomedical Sciences

Heart disease has been the leading cause of death in the United States for more than 90 years. The leading cause of death in individuals aged 65 and older has remained diseases of the heart from 1950 to the current time. According to the CDC, once diagnosed with heart disease, individuals have an approximately 50% chance of dying within 5 years, regardless of race. Mortality related to heart disease increased dramatically from the start of the 1900s to 1921, but subsequently experienced a steady decline from the mid-1960’s to 2000. However, when the decrease in heart disease is examined at the level of race it is clear that the decrease is not equally shared. While the leading cause of death among both Caucasian American men and women and African American men and women remains heart disease, the decrease in incidence of coronary heart disease among African American men was only half of the decrease in incidence among Caucasian American men. Genetic variants in BAG3 (Bcl-2 associated athanogene 3), a highly evolutionarily conserved gene that has recently emerged as a major dilated cardiomyopathy locus, are prevalent in isolated populations. This led us to hypothesize that variants in BAG3 might contribute to the increased prevalence of IDC in individuals of African ancestry. Expressed predominantly in the heart, the skeletal muscle and in many cancers, BAG3 has pleotropic effects in the heart. It inhibits apoptosis by binding to Bcl-2, facilitates protein quality control by binding to both large and small heat shock proteins, mediates adrenergic responsiveness by coupling the β-adrenergic receptor and the L-type Ca2+ channel, and maintains the integrity of the sarcomere by anchoring actin filaments to the Z disc. However, a paucity of subjects of African ancestry have been included in cohorts of probands with familial dilated cardiomyopathy whose exomes or genomes have been sequenced. Based on our previous observations and reports from other groups we postulated: 1) that mice with haplo-insufficiency of BAG3 will re-capitulate disease seen in humans and serve as a model for studying the pathogenesis of BAG3. 2) The prevalence or identification of specific BAG3 variants will differ by race and/or ethnicity. 3) SNVs of BAG3 may contribute to disease progression and thereby be pathogenic. Our study points out that we cannot understand population-based differences without enhancing the diversity of populations included in genomic studies. Similarly, in the era of big data, efforts must be undertaken to assess the genetic profile of both probands and their family members as without the ability to measure segregation, penetrance and plasticity we can only ascribe associations to functional genetic variants.

Temple University – Theses

Advisors/Committee Members: Feldman, Arthur M. (Arthur Michael);, Hamad, Eman, Koch, Walter J., Tilley, Douglas G., Khalili, Kamel;.

Subjects/Keywords: Cellular biology;

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Myers, V. (2018). The Role of BAG3 in the Failing Heart. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,490584

Chicago Manual of Style (16th Edition):

Myers, Valerie. “The Role of BAG3 in the Failing Heart.” 2018. Doctoral Dissertation, Temple University. Accessed July 02, 2020. http://digital.library.temple.edu/u?/p245801coll10,490584.

MLA Handbook (7th Edition):

Myers, Valerie. “The Role of BAG3 in the Failing Heart.” 2018. Web. 02 Jul 2020.

Vancouver:

Myers V. The Role of BAG3 in the Failing Heart. [Internet] [Doctoral dissertation]. Temple University; 2018. [cited 2020 Jul 02]. Available from: http://digital.library.temple.edu/u?/p245801coll10,490584.

Council of Science Editors:

Myers V. The Role of BAG3 in the Failing Heart. [Doctoral Dissertation]. Temple University; 2018. Available from: http://digital.library.temple.edu/u?/p245801coll10,490584

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