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You searched for +publisher:"University of North Carolina" +contributor:("Willis, Monte"). Showing records 1 – 3 of 3 total matches.

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University of North Carolina

1. Wadosky, Kristine Marie. Cardiac Muscle RING Finger 1 Inhibits Adaptive Hypertrophic Remodeling Induced by IGF-1, Exercise, and Thyroid Hormone.

Degree: 2014, University of North Carolina

In the face of cardiac load, the heart responds by undergoing hypertrophy. Under pathological conditions, ventricular wall thickening cannot be maintained, impairing function (heart failure). In contrast, ventricular wall thickening in response to physiological stimuli does not impair cardiac function. Pathological and physiological hypertrophy are driven by distinct signaling pathways – while vasoactive factors induce the former, growth hormones induce the latter. Understanding the mechanisms through which heart growth is adaptive has recently become a goal of cardiac research, in the hopes of using this information in the discovery of therapies that promote restoration of the myocardium following injury (since an effective treatment for heart failure has yet to be developed). The purpose of this dissertation work is to describe new mechanisms by which physiological cardiac hypertrophy is regulated. Signaling pathways activated in the heart following physiologic stimuli are receptor tyrosine kinases (RTKs) and nuclear receptors (NRs), of which the IGF-1/Akt and TRalpha; pathways, respectively, are most understood. The work presented here establishes the striated muscle specific ubiquitin ligase, Muscle RING finger 1 (MuRF1) as a novel regulator of physiological cardiac hypertrophy through its ubiquitination of transcription factors. MuRF1 inhibits cardiomyocyte growth in response to IGF-1 and aerobic exercise stimulation by poly-ubiquitinating and promoting the degradation of c-Jun, recently discovered to drive transcriptional expression of genes coding for members of the IGF-1 signaling cascade. In contrast, MuRF1 mono-ubiquitinates TRalpha; thereby inhibiting TRalpha transcriptional activity and thyroid hormone (TH)-dependent cardiac hypertrophy. Furthermore, it is established here that mono-ubiquitination of TRalpha by MuRF1 induces TRalpha accumulation in the cardiomyocyte nucleus where TRalpha interacts with centrosome-associated protein 350 (CAP350). This inhibitory mechanism, while being established for other NRs, is completely novel for TRalpha and has never been described in the heart. Altogether, this dissertation contributes to the field of cardiac growth research by detailing the discovery of an inhibitor of not one, but two, signaling pathways that stimulate beneficial cardiac hypertrophy. Given that MuRF1 inhibits both IGF-1/Akt and TRalpha signaling, the activity of this ubiquitin ligase may be as efficacious target for new cardiac therapies by virtue of MuRF1's widespread influence on the cardiomyocyte. Advisors/Committee Members: Wadosky, Kristine Marie, Willis, Monte.

Subjects/Keywords: School of Medicine; Curriculum in Genetics and Molecular Biology

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

APA (6th Edition):

Wadosky, K. M. (2014). Cardiac Muscle RING Finger 1 Inhibits Adaptive Hypertrophic Remodeling Induced by IGF-1, Exercise, and Thyroid Hormone. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:9b22c994-0047-4b44-8003-a5409ec09f3b

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Wadosky, Kristine Marie. “Cardiac Muscle RING Finger 1 Inhibits Adaptive Hypertrophic Remodeling Induced by IGF-1, Exercise, and Thyroid Hormone.” 2014. Thesis, University of North Carolina. Accessed October 27, 2020. https://cdr.lib.unc.edu/record/uuid:9b22c994-0047-4b44-8003-a5409ec09f3b.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Wadosky, Kristine Marie. “Cardiac Muscle RING Finger 1 Inhibits Adaptive Hypertrophic Remodeling Induced by IGF-1, Exercise, and Thyroid Hormone.” 2014. Web. 27 Oct 2020.

Vancouver:

Wadosky KM. Cardiac Muscle RING Finger 1 Inhibits Adaptive Hypertrophic Remodeling Induced by IGF-1, Exercise, and Thyroid Hormone. [Internet] [Thesis]. University of North Carolina; 2014. [cited 2020 Oct 27]. Available from: https://cdr.lib.unc.edu/record/uuid:9b22c994-0047-4b44-8003-a5409ec09f3b.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Wadosky KM. Cardiac Muscle RING Finger 1 Inhibits Adaptive Hypertrophic Remodeling Induced by IGF-1, Exercise, and Thyroid Hormone. [Thesis]. University of North Carolina; 2014. Available from: https://cdr.lib.unc.edu/record/uuid:9b22c994-0047-4b44-8003-a5409ec09f3b

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation


University of North Carolina

2. Li, Jin. Genetic association studies: application in the investigation of biomarkers related to cardiovascular diseases and study design.

Degree: 2015, University of North Carolina

Cardiovascular disease (CVD) is the No. 1 cause of death in the United States, killing about 610,000 people every year. Biomarkers are important tools to identify vulnerable individuals at high risk of CVD. Investigation of the genetic architecture for biomarkers and other risk factors related to CVD is of critical importance in the prevention and treatment of CVD. For my first chapter, I conducted genome-wide admixture and association studies for iron-related traits in 2347 African Americans (AAs) participants from the Jackson Heart Study (JHS). I identified, for the first time, a second independent genome-wide significant signal in the TF region associated with total iron binding capacity levels. I also identified a novel functional missense variant in the G6PD-GAB3 region significantly associated with ferritin levels. Both results were replicated in a second AA cohort with iron measures. For my second chapter, I conducted genome-wide admixture and association studies, and gene-based exome-wide association studies of rare variants, to identify variants or genes, harboring a high burden of rare functional variants, associated with lipoprotein(a) [Lp(a)] cholesterol levels in 2895 AAs participating in the JHS. I observed significant evidence for association between Lp(a) and both local ancestry and hundreds variants spanning ~10Mb the LPA gene region on chromosome 6q. Of note, the region containing associated variants became much narrower, centered over the LPA gene (<1Mb), after adjusting for local ancestry. I also observed a single significant non-synonymous SNP in APOE and a high burden of coding variants in LPA and APOE significantly associated with Lp(a) levels For my third chapter, I investigated the genetic association of four candidate variants with blood pressure and tested the modifying effects of environmental factors in 7,319 Chinese adults from the China Nutrition and Health Survey (CHNS). I observed that rs1458038 exhibited a significant genotype-by-BMI interaction affecting blood pressure measures, with the strongest variant effects in those with the highest BMI. Finally, for my last chapter, I described a multistage GWAS study design that uses selective phenotyping to increase power for studies with existing genome-wide genotypic data and to-be-measured quantitative phenotypes that are under a sample-size constraint. The approach uses simulated annealing to identify the optimal subset of subjects to be phenotyped in Stage 2 of a two-stage GWAS. I showed that our approach has greater statistical power than the conventional approach of randomly selecting a subset of subjects for phenotyping. We demonstrate the gains in power for both directly genotyped and imputed genetic variants. Together, these studies further our understanding of the genetic architecture of risk factors for CVD, suggest some candidates for future genetic and molecular studies, and also shed some light on the study design of future large-scale genetic association studies where the cost constraints will be determined by the expense of… Advisors/Committee Members: Li, Jin, Lange, Ethan, Lange, Leslie, Li, Yun, Mohlke, Karen, Willis, Monte.

Subjects/Keywords: Bioinformatics; School of Medicine; Curriculum in Bioinformatics and Computational Biology

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APA (6th Edition):

Li, J. (2015). Genetic association studies: application in the investigation of biomarkers related to cardiovascular diseases and study design. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:0a49c966-a4de-40c2-bad5-601c1bf7503e

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Li, Jin. “Genetic association studies: application in the investigation of biomarkers related to cardiovascular diseases and study design.” 2015. Thesis, University of North Carolina. Accessed October 27, 2020. https://cdr.lib.unc.edu/record/uuid:0a49c966-a4de-40c2-bad5-601c1bf7503e.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Li, Jin. “Genetic association studies: application in the investigation of biomarkers related to cardiovascular diseases and study design.” 2015. Web. 27 Oct 2020.

Vancouver:

Li J. Genetic association studies: application in the investigation of biomarkers related to cardiovascular diseases and study design. [Internet] [Thesis]. University of North Carolina; 2015. [cited 2020 Oct 27]. Available from: https://cdr.lib.unc.edu/record/uuid:0a49c966-a4de-40c2-bad5-601c1bf7503e.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Li J. Genetic association studies: application in the investigation of biomarkers related to cardiovascular diseases and study design. [Thesis]. University of North Carolina; 2015. Available from: https://cdr.lib.unc.edu/record/uuid:0a49c966-a4de-40c2-bad5-601c1bf7503e

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation


University of North Carolina

3. Melehani, Jason. Mechanisms and consequences of Staphylococcus aureus Leukocidin AB-mediated activation of the host NLRP3 inflammasome.

Degree: Pharmacology, 2016, University of North Carolina

The NLRP3 inflammasome is a critical innate immune sensor implicated in the pathogenesis of dozens of infectious and non-infectious diseases. Activation of the NLRP3 inflammasome causes IL-1β and IL-18 secretion and necrotic cell death. Staphylococcus aureus is a common cause of infections in humans. S. aureus produces a family of pore-forming toxins that are cytotoxic to human immune cells. One recently discovered pore-forming toxin, Leukocidin AB, is the focus of studies herein. Leukocidin AB is a human-specific, pore-forming toxin that binds CD11b to initiate pore formation. In order to characterize the mechanism of Leukocidin AB cytotoxicity and determine its significance, we evaluated the effects of Leukocidin AB on primary human monocytes and THP1 monocytic cells. Leukocidin AB was one of the most potent toxins in killing primary human monocytes. In THP1 cells, knockdown of NLRP3 or ASC by shRNA diminished Leukocidin AB-induced cytotoxicity and prevented secretion of IL-1β and IL-18. We also characterized the NLRP3 inflammasome in bacterial survival during phagocytosis. When S. aureus was phagocytosed by THP1 cells, LukAB triggered IL-1β secretion and cell death. shRNA-mediated depletion of NLRP3 or ASC suppressed IL-1β secretion but had no effect on Leukocidin AB-induced cell death. These data suggest that a separate mechanism is responsible for triggering cell death when Leukocidin AB binds CD11b on the phagosome membrane instead of the plasma membrane. We also initiated studies to characterize the role of kinases and phosphorylation in the response to Leukocidin AB. Using multiplex inhibitor bead chromatography and quantitative mass spectrometry, we identified eight kinases that rapidly decrease in activity during Leukocidin AB exposure. We demonstrated a role for Death-Associated Protein Kinase in the response to Leukocidin AB by showing that its inhibition suppressed Leukocidin AB-induced cytokine secretion and cytotoxicity. And finally, we used a novel transfection method for overexpressing mutant proteins in THP1 cells to show that the NLRP3 S198D/S201D mutant could spontaneously activate NLRP3 inflammasome signaling. In total, these studies make significant contributions to the understanding of S. aureus pathogenesis and the regulation of innate immune NLRP3 inflammasome signaling in response to a human specific, S. aureus pore-forming toxin. Advisors/Committee Members: Melehani, Jason, Duncan, Joseph, Nicholas, Robert, Doerschuk, Claire, Willis, Monte, Johnson, Gary.

Subjects/Keywords: School of Medicine; Department of Pharmacology

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

APA (6th Edition):

Melehani, J. (2016). Mechanisms and consequences of Staphylococcus aureus Leukocidin AB-mediated activation of the host NLRP3 inflammasome. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:f98e7df6-408e-40db-8202-8ab65dd52e01

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Melehani, Jason. “Mechanisms and consequences of Staphylococcus aureus Leukocidin AB-mediated activation of the host NLRP3 inflammasome.” 2016. Thesis, University of North Carolina. Accessed October 27, 2020. https://cdr.lib.unc.edu/record/uuid:f98e7df6-408e-40db-8202-8ab65dd52e01.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Melehani, Jason. “Mechanisms and consequences of Staphylococcus aureus Leukocidin AB-mediated activation of the host NLRP3 inflammasome.” 2016. Web. 27 Oct 2020.

Vancouver:

Melehani J. Mechanisms and consequences of Staphylococcus aureus Leukocidin AB-mediated activation of the host NLRP3 inflammasome. [Internet] [Thesis]. University of North Carolina; 2016. [cited 2020 Oct 27]. Available from: https://cdr.lib.unc.edu/record/uuid:f98e7df6-408e-40db-8202-8ab65dd52e01.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Melehani J. Mechanisms and consequences of Staphylococcus aureus Leukocidin AB-mediated activation of the host NLRP3 inflammasome. [Thesis]. University of North Carolina; 2016. Available from: https://cdr.lib.unc.edu/record/uuid:f98e7df6-408e-40db-8202-8ab65dd52e01

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

.