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You searched for +publisher:"Temple University" +contributor:("Elrod, John W.;"). Showing records 1 – 3 of 3 total matches.

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Temple University

1. Hoffman, Nicholas. Mitochondrial Calcium Influx is Determined by Multiple Protein Components Including SLC25A23 and MICU1.

Degree: PhD, 2014, Temple University

Biochemistry

Ca2+ control mechanisms employed by the cell at the plasma membrane include receptor operated, voltage-sensitive, and store operated channels for Ca2+ import. Upon entry into the cytosol, Ca2+ is sequestered by Ca2+ binding proteins, the endoplasmic reticulum (ER), or by mitochondria. The largest Ca2+ store in the cell is the ER where Ca2+ levels approach millimolar levels. The ER regulates cytosolic Ca2+ homeostasis by using Ca2+ binding proteins, the SERCA pump, second messenger Ca2+ release upon IP3 receptor activation, and Ca2+-induced Ca2+ release by ryanodine receptors. Basal cytosolic Ca2+ levels are maintained at around 100nM. The mitochondria begins clearing GPRC-depended cytosolic Ca2+elevation after a short time delay during which the cytosolic Ca2+ concentration exceeds 3M. Then, the mitochondria sacrifices a portion of its membrane potential to drive Ca2+ influx across the mitochondrial inner membrane into the matrix. The membrane potential of the mitochondria is created in part by the electron transport, which while transferring electrons, ejects protons from the matrix to the inner membrane space. The rapid mitochondrial Ca2+ uptake decreases mitochondrial membrane potential thus reducing or fully collapsing the mitochondria's ability to generate ATP. This uncoupling of the electron transport chain results in ROS production and decreased cell survival. Mitochondria provide the body with energy that allows a heart to beat, a brain to store memories, and fuels locomotive function. As a stand-alone energy generator, the mitochondria would be interesting, but not dynamic. The dynamic flow of information to the mitochondria through Ca2+ signaling with all the components of symbiotic precision is a true biological phenomenon. In the mitochondria, a complex Ca2+ buffering system of channels, pores, and exchangers directly affects the conversion of chemical potential to ATP. Recent, discoveries of the Ca2+ uniporter (MCU) and other system components have provided the tools to tackle levels of mitochondrion physiologic studies that were not possible only a couple of years ago. There remains a great need for advancement in the understanding of mitochondrial bioenergetics, and undoubtedly, the mitochondria will be viewed as a determinant factor for survival. The mitochondrial inner membrane through its curious construction of 3:1 protein to lipid ratio, carefully regulates the permeability of ions and metabolites. The transport of Ca2+ and other small ions across the inner membrane is an essential signaling pathway for mitochondrial maintenance of metabolic functions, but the mechanisms are still unclear due to a lack of mitochondrial systems biology. For example, the oligomeric MCU with two transmembrane domains is a core component of the major Ca2+ import pathway in mitochondria, and ablation of MCU lowers mitochondrial Ca2+ uptake, however portions such as the highly conserved linker between the two transmembrane was unstudied until recently. Other complex components such as MICU1 and…

Advisors/Committee Members: Muniswamy, Madesh;, Soboloff, Jonathan, Haines, Dale, Elrod, John W., Sheu, Shey-Shing;.

Subjects/Keywords: Biochemistry

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APA (6th Edition):

Hoffman, N. (2014). Mitochondrial Calcium Influx is Determined by Multiple Protein Components Including SLC25A23 and MICU1. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,287159

Chicago Manual of Style (16th Edition):

Hoffman, Nicholas. “Mitochondrial Calcium Influx is Determined by Multiple Protein Components Including SLC25A23 and MICU1.” 2014. Doctoral Dissertation, Temple University. Accessed July 02, 2020. http://digital.library.temple.edu/u?/p245801coll10,287159.

MLA Handbook (7th Edition):

Hoffman, Nicholas. “Mitochondrial Calcium Influx is Determined by Multiple Protein Components Including SLC25A23 and MICU1.” 2014. Web. 02 Jul 2020.

Vancouver:

Hoffman N. Mitochondrial Calcium Influx is Determined by Multiple Protein Components Including SLC25A23 and MICU1. [Internet] [Doctoral dissertation]. Temple University; 2014. [cited 2020 Jul 02]. Available from: http://digital.library.temple.edu/u?/p245801coll10,287159.

Council of Science Editors:

Hoffman N. Mitochondrial Calcium Influx is Determined by Multiple Protein Components Including SLC25A23 and MICU1. [Doctoral Dissertation]. Temple University; 2014. Available from: http://digital.library.temple.edu/u?/p245801coll10,287159


Temple University

2. Woodall, Benjamin Philip. NOVEL ROLES FOR GRK2 IN METABOLIC HOMEOSTASIS AND SKELETAL MUSCLE PHYSIOLOGY.

Degree: PhD, 2016, Temple University

Biomedical Sciences

Over the past two decades, a vast body of research has demonstrated the importance of G protein-coupled receptor kinase 2 (GRK2) in the physiology and pathophysiology of the heart. Adrenergic receptors are the primary target for GRK2 activity in the heart; phosphorylation by GRK2 leads to desensitization of these receptors. As such, levels of GRK2 activity in the heart directly correlate with cardiac contractile function. Furthermore, increased expression of GRK2 following cardiac insult exacerbates injury and speeds progression to heart failure. In this dissertation we turned our attention towards two novel aspects of GRK2 biology. Firstly, despite the importance of this GRK2 activity in both the physiology and pathophysiology of the heart, relatively little is known about the role of GRK2 in skeletal muscle function and disease. In the first study of this dissertation, we generated a novel skeletal muscle specific GRK2 knockout (KO) mouse (MLC-Cre:GRK2fl/fl) to gain a better understanding of the role of GRK2 in skeletal muscle physiology. In isolated muscle mechanics testing, GRK2 ablation caused a significant decrease in the specific force of contraction of the fast-twitch extensor digitorum longus muscle, yet had no effect on the slow-twitch soleus muscle. Despite these effects in isolated muscle, exercise capacity was not altered in MLC-Cre:GRK2fl/fl mice compared to wild-type controls. Skeletal muscle hypertrophy stimulated by clenbuterol, a β2-adrenergic receptor agonist, was significantly enhanced in MLC-Cre:GRK2fl/fl mice; mechanistically, this seems to be due to increased clenbuterol-stimulated pro-hypertrophic Akt signaling in the GRK2 KO skeletal muscle. In summary, this study provides the first insights into the role of GRK2 in skeletal muscle physiology, and points to a role for GRK2 as a modulator of contractile properties in skeletal muscle as well as β2-adrenergic receptor-induced hypertrophy. In the second part of this dissertation, we report surprising novel metabolic phenotypes that arise from modulating GRK2 activity exclusively in the heart. We show that transgenic βARKct (TgβARKct) mice (cardiac specific expression of a GRK2 inhibitory peptide) are more susceptible to high-fat diet (HFD) induced obesity. TgβARKct mice exhibit marked increase in adiposity on HFD relative to control animals. Conversely transgenic GRK2 mice (TgGRK2) mice (cardiac specific overexpression of GRK2) show resistance to weight gain on a HFD and decrease in adipose tissue mass relative to control animals. Furthermore, conditioned media from βARKct expressing neonatal rat ventricular myocytes enhances adipocyte differentiation in vitro. These results suggest that the heart produces a secreted factor to control whole body metabolism, and that GRK2 is a regulator of this mechanism.

Temple University – Theses

Advisors/Committee Members: Koch, Walter J.;, Drosatos, Konstantinos, Elrod, John W., Tilley, Douglas G., Rao, Ajay D.;.

Subjects/Keywords: Molecular biology;

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

APA (6th Edition):

Woodall, B. P. (2016). NOVEL ROLES FOR GRK2 IN METABOLIC HOMEOSTASIS AND SKELETAL MUSCLE PHYSIOLOGY. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,391153

Chicago Manual of Style (16th Edition):

Woodall, Benjamin Philip. “NOVEL ROLES FOR GRK2 IN METABOLIC HOMEOSTASIS AND SKELETAL MUSCLE PHYSIOLOGY.” 2016. Doctoral Dissertation, Temple University. Accessed July 02, 2020. http://digital.library.temple.edu/u?/p245801coll10,391153.

MLA Handbook (7th Edition):

Woodall, Benjamin Philip. “NOVEL ROLES FOR GRK2 IN METABOLIC HOMEOSTASIS AND SKELETAL MUSCLE PHYSIOLOGY.” 2016. Web. 02 Jul 2020.

Vancouver:

Woodall BP. NOVEL ROLES FOR GRK2 IN METABOLIC HOMEOSTASIS AND SKELETAL MUSCLE PHYSIOLOGY. [Internet] [Doctoral dissertation]. Temple University; 2016. [cited 2020 Jul 02]. Available from: http://digital.library.temple.edu/u?/p245801coll10,391153.

Council of Science Editors:

Woodall BP. NOVEL ROLES FOR GRK2 IN METABOLIC HOMEOSTASIS AND SKELETAL MUSCLE PHYSIOLOGY. [Doctoral Dissertation]. Temple University; 2016. Available from: http://digital.library.temple.edu/u?/p245801coll10,391153


Temple University

3. Luongo, Timothy Scott. The Role of Mitochondrial Calcium Exchange in Cardiac Physiology and Disease.

Degree: PhD, 2017, Temple University

Biomedical Sciences

The high metabolic demand of the heart makes it essential that an efficient and tightly controlled system be in place to regulate energy production. Contractility is mediated by a variable flux in intracellular calcium (iCa2+), which is proposed to be integrated into mitochondria to regulate cardiac energetics. Moreover, mitochondrial Ca2+ (mCa2+)-overload is known to activate the mitochondrial permeability transition pore (MPTP) and induce cell death. However, the true function of cardiac mCa2+ in physiology remains unknown. Recent studies have reported that the Mcu gene encodes the channel-forming portion of the mitochondrial calcium uniporter (MCU) and is required for mCa2+ uptake (Baughman et al., 2011; De Stefani, Raffaello, Teardo, Szabo, & Rizzuto, 2011). To examine the role of mCa2+ in the heart, we generated a conditional, cardiac-specific knockout model and deleted Mcu in adult mice (Mcu-cKO). Loss of Mcu protected against myocardial ischemia-reperfusion (IR) (40 min occlusion of the left coronary artery (LCA) followed by 24h reperfusion) injury by preventing the activation of the MPTP. We observed a 45% reduction in infarct size per area-at-risk and a 65% reduction in cardiac troponin-I serum levels from 24h post-IR. In addition, while we found no baseline phenotype or change in baseline mCa2+ content, Mcu-cKO mice lacked contractile responsiveness to β-adrenergic receptor stimulation (isoproterenol infusion) as assessed by invasive hemodynamics, and, in parallel, were unable to activate mitochondrial dehydrogenases, thereby decreasing tricarboxylic acid (TCA) cycle flux and cardiac NADH. We found that Mcu-cKO mice had a 3-fold increase in pyruvate dehydrogenase (PDH) phosphorylation and a 50% decrease in PDH activity post-isoproterenol infusion. Further experimental analyses in isolated adult cardiomyocytes confirmed a lack of energetic responsiveness to acute sympathetic stress (isoproterenol failure to mediate an increase in oxidative phosphorylation capacity) supporting the hypothesis that the physiological function of the MCU in the heart is to modulate Ca2+-dependent metabolism during the ‘fight or flight’ response. However, questions still remain on how basal mCa2+ levels are regulated and if it contributes to cardiac disease. The mitochondrial sodium/calcium exchanger (mNCX) is hypothesized as the primary mechanism of mCa2+ efflux, but to date no study has confirmed its identity or function in an in vivo system (Palty et al., 2010). To investigate the role of mNCX in the heart, we generated mutant mice with loxP sites flanking exons 5-7 of the candidate gene, Slc8b1, and crossed them with a tamoxifen-inducible, cardiomyocyte-specific, αMHC-Cre mouse to delete mNCX in the adult heart (mNCX-cKO). Biophysical study of cardiomyocytes isolated from mNCX-cKO mice revealed a significant reduction in mCa2+ efflux rate. Tamoxifen-induced deletion of Slc8b1 in adult hearts caused sudden death with less than 15% of mice surviving after 10 days. Echocardiographic evaluation of mNCX-cKO…

Advisors/Committee Members: Elrod, John W.;, Koch, Walter J., Madesh, Muniswamy, Houser, Steven R., Murphy, Elizabeth;.

Subjects/Keywords: Molecular biology; Cellular biology; Physiology;

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

APA (6th Edition):

Luongo, T. S. (2017). The Role of Mitochondrial Calcium Exchange in Cardiac Physiology and Disease. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,437718

Chicago Manual of Style (16th Edition):

Luongo, Timothy Scott. “The Role of Mitochondrial Calcium Exchange in Cardiac Physiology and Disease.” 2017. Doctoral Dissertation, Temple University. Accessed July 02, 2020. http://digital.library.temple.edu/u?/p245801coll10,437718.

MLA Handbook (7th Edition):

Luongo, Timothy Scott. “The Role of Mitochondrial Calcium Exchange in Cardiac Physiology and Disease.” 2017. Web. 02 Jul 2020.

Vancouver:

Luongo TS. The Role of Mitochondrial Calcium Exchange in Cardiac Physiology and Disease. [Internet] [Doctoral dissertation]. Temple University; 2017. [cited 2020 Jul 02]. Available from: http://digital.library.temple.edu/u?/p245801coll10,437718.

Council of Science Editors:

Luongo TS. The Role of Mitochondrial Calcium Exchange in Cardiac Physiology and Disease. [Doctoral Dissertation]. Temple University; 2017. Available from: http://digital.library.temple.edu/u?/p245801coll10,437718

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