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University of North Carolina
1.
Nesmith, Jessica.
Investigation of Flt1 and VEGF signaling in connections during sprouting angiogenesis.
Degree: 2016, University of North Carolina
URL: https://cdr.lib.unc.edu/record/uuid:fa212e56-c40b-4749-bdd2-ef1f2b289a1c 
► Blood vessel formation is essential for vertebrate development and is primarily achieved by angiogenesis, the sprouting of endothelial cells from pre-existing vessels. Vessel networks expand…
(more)
▼ Blood vessel formation is essential for vertebrate development and is primarily achieved by angiogenesis, the sprouting of endothelial cells from pre-existing vessels. Vessel networks expand when sprouts form new connections, a process whose regulation is poorly understood. Here we show that vessel anastomosis is spatially regulated by VEGFR1 (Flt1), a VEGF-A receptor that acts as a ligand decoy receptor. Expanding vessel networks in vivo favor interactions with flt-1 mutant endothelial cells. Live imaging in vitro revealed that stable connections are preceded by transient contacts from extending sprouts, suggesting sampling of potential target sites, and reduction of Flt1 reduced transient contacts. Endothelial cells at target sites with elevated protrusive activity and/or reduced Flt1 were more likely to form stable connections with incoming sprouts. Target cells with reduced membrane-localized Flt1 (mFlt1), but not soluble Flt1, recapitulated the bias towards stable connections, suggesting that relative mFlt1 expression spatially influences selection of stable connections. Thus multiple sprout anastomosis parameters are regulated by VEGF signaling, and stable connections are spatially regulated by endothelial cell-intrinsic modulation of mFlt1, suggesting new ways to manipulate how vessel networks formation.
Advisors/Committee Members: Nesmith, Jessica, Goldstein, Bob, Bautch, Victoria, Caron, Kathleen, Conlon, Frank, Liu, Jiandong.
Subjects/Keywords: School of Medicine; Curriculum in Genetics and Molecular Biology
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APA (6th Edition):
Nesmith, J. (2016). Investigation of Flt1 and VEGF signaling in connections during sprouting angiogenesis. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:fa212e56-c40b-4749-bdd2-ef1f2b289a1c
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):
Nesmith, Jessica. “Investigation of Flt1 and VEGF signaling in connections during sprouting angiogenesis.” 2016. Thesis, University of North Carolina. Accessed January 16, 2021.
https://cdr.lib.unc.edu/record/uuid:fa212e56-c40b-4749-bdd2-ef1f2b289a1c.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Nesmith, Jessica. “Investigation of Flt1 and VEGF signaling in connections during sprouting angiogenesis.” 2016. Web. 16 Jan 2021.
Vancouver:
Nesmith J. Investigation of Flt1 and VEGF signaling in connections during sprouting angiogenesis. [Internet] [Thesis]. University of North Carolina; 2016. [cited 2021 Jan 16].
Available from: https://cdr.lib.unc.edu/record/uuid:fa212e56-c40b-4749-bdd2-ef1f2b289a1c.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Nesmith J. Investigation of Flt1 and VEGF signaling in connections during sprouting angiogenesis. [Thesis]. University of North Carolina; 2016. Available from: https://cdr.lib.unc.edu/record/uuid:fa212e56-c40b-4749-bdd2-ef1f2b289a1c
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of North Carolina
2.
Samsa, Leigh.
Molecular Regulation of Zebrafish Cardiac Maturation.
Degree: Cell Biology and Physiology, 2016, University of North Carolina
URL: https://cdr.lib.unc.edu/record/uuid:8bfab635-a045-44fe-a101-1c391003dda1
► Congenital heart diseases (CHDs) are the most common type of human birth defect and often feature structural abnormalities that arise during development and maturation. Many…
(more)
▼ Congenital heart diseases (CHDs) are the most common type of human birth defect and often feature structural abnormalities that arise during development and maturation. Many CHDs have a genetic component which provides a molecular basis for the cellular defects underlying structural malformations. During embryonic development, the vertebrate heart expands and remodels to meet the cardiovascular needs of the developing embryo in a process called cardiac maturation. In particular, the ventricular chamber matures to optimize the internal architecture for efficient conduction and contraction. Chamber maturation features formation of luminal muscular protrusions, called trabeculae, which increase myocardial mass and are often malformed in CHD. Here, zebrafish (Danio rerio) are used as an optically accessible, genetically tractable, vertebrate model to explore the conserved, molecular basis of chamber maturation Accumulating evidence indicates a critical role for cardiac contraction and the resulting fluid forces in shaping the developing heart, yet the molecular basis of this function is largely unknown. Data reported in Chapter 2 describe an essential role for cardiac contraction-responsive transcriptional changes in endocardial cells for regulating trabeculation. Cardiac contraction causes blood flow, which is likely mechanotransduced into intracellular signaling cues by endocardial primary cilia. Contraction stimulates notch1b transcription, and Notch1 activation induces expression of downstream genes ephrinb2a (efnb2a) and neuregulin-1 (nrg1) in the endocardium. Forced Notch activation rescues efnb2a and nrg1 expression in non-contractile hearts, and efnb2a is essential for trabeculation. Although ErbB2 receptor tyrosine-protein (ErbB2), an essential receptor partner in the Nrg1-ErbB2/ErbB4 signaling pathway, is necessary to stimulate trabeculation in mice and zebrafish, requirement for nrg1 has not been explored in zebrafish. In Chapter 3, CRISPR/Cas9 targeted gene editing was used to generate novel, isoform-specific mutations in nrg1. Phenotypic analysis of nrg1 mutants revealed that nrg1 is dispensable for cardiac trabeculation. However, one isoform, nrg1-III is essential for establishing the cardiac nerve plexus. Likely as a consequence of impaired cardiac innervation, nrg1 mutants have cardiac malformations and experience early mortality. In sum, this study reveals previously uncharacterized cellular and molecular relationships regulating chamber maturation.
Advisors/Committee Members: Samsa, Leigh, Liu, Jiandong, Caron, Kathleen, Dudley, Andrew, Faber, James, Bautch, Victoria, Conlon, Frank.
Subjects/Keywords: School of Medicine; Department of Cell Biology and Physiology
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APA ·
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APA (6th Edition):
Samsa, L. (2016). Molecular Regulation of Zebrafish Cardiac Maturation. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:8bfab635-a045-44fe-a101-1c391003dda1
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):
Samsa, Leigh. “Molecular Regulation of Zebrafish Cardiac Maturation.” 2016. Thesis, University of North Carolina. Accessed January 16, 2021.
https://cdr.lib.unc.edu/record/uuid:8bfab635-a045-44fe-a101-1c391003dda1.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Samsa, Leigh. “Molecular Regulation of Zebrafish Cardiac Maturation.” 2016. Web. 16 Jan 2021.
Vancouver:
Samsa L. Molecular Regulation of Zebrafish Cardiac Maturation. [Internet] [Thesis]. University of North Carolina; 2016. [cited 2021 Jan 16].
Available from: https://cdr.lib.unc.edu/record/uuid:8bfab635-a045-44fe-a101-1c391003dda1.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Samsa L. Molecular Regulation of Zebrafish Cardiac Maturation. [Thesis]. University of North Carolina; 2016. Available from: https://cdr.lib.unc.edu/record/uuid:8bfab635-a045-44fe-a101-1c391003dda1
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of North Carolina
3.
Battista, Nicholas.
The Fluid Dynamics of Heart Development: The effect of morphology on flow at several stages.
Degree: Mathematics, 2017, University of North Carolina
URL: https://cdr.lib.unc.edu/record/uuid:10c652c0-5884-47f8-95b6-ce38502bcc66
► Proper cardiogenesis requires a delicate balance between genetic and environmental (epigenetic) signals, and mechanical forces. While many cellular biologists and geneticists have extensively studied heart…
(more)
▼ Proper cardiogenesis requires a delicate balance between genetic and environmental (epigenetic) signals, and mechanical forces. While many cellular biologists and geneticists have extensively studied heart morphogenesis using various experimental techniques, only a few scientists have begun using mathematical modeling as a tool for studying cardiogenic events. Hemodynamic processes, such as vortex formation, are important in the generation of shear at the endothelial surface layer and strains at the epithelial layer, which aid in proper morphology and functionality. The purpose of this thesis is to study the underlying fluid dynamics in various stages on heart development, in particular, the morphogenic stages when the heart is a linear heart tube as well as during the onset of ventricular trabeculation. Previous mathematical models of the linear heart tube stage have focused on mechanisms of valveless pumping, whether dynamic suction pumping (impedance pumping) or peristalsis; however, they all have neglected hematocrit. The impact of blood cells was examined by fluid-structure interaction simulations, via the immersed boundary method. Moreover, electrophysiology models were incorporated into an immersed boundary framework, and bifurcations within the morphospace were studied that give rise to a spectrum of pumping regimes, with peristaltic-like waves of contraction and impedance pumping at the extremes. Lastly, effects of resonant pumping, damping, and boundary inertial effects (added mass) were studied for dynamic suction pumping. The other stage of heart development considered here is during the onset of ventricular trabeculation. This occurs after the heart has undergone the cardiac looping stage and now is a multi-chambered pumping system with primitive endocardial cushions, which act as precursors to valve leaflets. Trabeculation introduces complex morphology onto the inner lining of the endocardium in the ventricle. This transition of a smooth endocardium to one with complex geometry, may have significant effect on the intracardial fluid dynamics and stress distribution within emrbyonic hearts. Previous studies have not included these geometric perturbations along the ventricular endocardium. The role of trabeculae on intracardial (and intertrabecular) flows was studied using two different mathematical models implemented within an immersed boundary framework. It is shown that the trabecular geometry and number density have a significant effect on such flows. Furthermore this thesis also focused attention to the creation of software for scientists and engineers to perform fluid-structure interaction simulations at an accelerated rate, in user-friendly environments for beginner programmers, e.g., MATLAB or Python 3.5. The software, IB2d, performs fully coupled fluid-structure interaction problems using Charles Peskin's immersed boundary method. IB2d is capable of running a vast range of biomechanics models and contains multiple options for constructing material properties of the fiber structure,…
Advisors/Committee Members: Battista, Nicholas, Miller, Laura, Forest, M. Gregory, Griffith, Boyce, Klotsa, Daphne, Liu, Jiandong.
Subjects/Keywords: College of Arts and Sciences; Department of Mathematics
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APA ·
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MLA ·
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Manager
APA (6th Edition):
Battista, N. (2017). The Fluid Dynamics of Heart Development: The effect of morphology on flow at several stages. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:10c652c0-5884-47f8-95b6-ce38502bcc66
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):
Battista, Nicholas. “The Fluid Dynamics of Heart Development: The effect of morphology on flow at several stages.” 2017. Thesis, University of North Carolina. Accessed January 16, 2021.
https://cdr.lib.unc.edu/record/uuid:10c652c0-5884-47f8-95b6-ce38502bcc66.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Battista, Nicholas. “The Fluid Dynamics of Heart Development: The effect of morphology on flow at several stages.” 2017. Web. 16 Jan 2021.
Vancouver:
Battista N. The Fluid Dynamics of Heart Development: The effect of morphology on flow at several stages. [Internet] [Thesis]. University of North Carolina; 2017. [cited 2021 Jan 16].
Available from: https://cdr.lib.unc.edu/record/uuid:10c652c0-5884-47f8-95b6-ce38502bcc66.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Battista N. The Fluid Dynamics of Heart Development: The effect of morphology on flow at several stages. [Thesis]. University of North Carolina; 2017. Available from: https://cdr.lib.unc.edu/record/uuid:10c652c0-5884-47f8-95b6-ce38502bcc66
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of North Carolina
4.
Mangum, Kevin.
Genetic and Epigenetic Mechanisms Regulating Smooth Muscle Cell Differentiation.
Degree: Pathology and Laboratory Medicine, 2017, University of North Carolina
URL: https://cdr.lib.unc.edu/record/uuid:3e390865-999e-44be-b0f8-91bcda14f410
► Smooth muscle differentiation is a complex process, involving numerous molecular, genetic, and epigenetic mechanisms. Notably, smooth muscle cells (SMCs) retain marked plasticity in their ability…
(more)
▼ Smooth muscle differentiation is a complex process, involving numerous molecular, genetic, and epigenetic mechanisms. Notably, smooth muscle cells (SMCs) retain marked plasticity in their ability to convert between synthetic and more differentiated contractile gene programs. In vascular diseases, including hypertension, atherosclerosis, and restenosis, SMCs dedifferentiate from their healthy, mature state to a more immature “phenotypically modulated” cell type capable of migrating, proliferating, and producing extracellular matrix, all of which contribute to disease. Additionally, genetic alterations in various components of the smooth muscle transcriptional machinery result in cardiovascular disease and even death. Thus, a more complete understanding of the exact mechanisms regulating SMC differentiation is crucial for the development of novel targets in the diagnosis and treatment of vascular disease. The work herein interrogates several points along the RhoA axis and defines their roles in SMC differentiation. First, the genetic and epigenetic mechanisms regulating expression of a smooth muscle-specific gene, GRAF3, are uncovered. GRAF3, also referred to as ARHGAP42, was first described by my collaborators in Joan Taylor’s Lab as a smooth muscle selective Rho-GAP essential for blood pressure control in mice. Single nucleotide polymorphisms in the GRAF3 gene were associated with changes in blood pressure, and the rs604723 T-allele variant located in a highly conserved DHS increased GRAF3 expression by promoting SRF binding to this region. In addition to SRF, we show that the transcription activity of this region as well as GRAF3 expression are controlled by the transcription factors, RBPJ and TEAD1. In subsequent chapters, we describe novel mechanisms regulating function of MRTF-A. Given that MRTF-A is essential for full activation of smooth muscle-specific gene expression, we hypothesize that these newly identified mechanisms regulate SMC differentiation. We describe our approach for identifying post-translational modifications and binding partners that regulate MRTF-A function. In our search for novel MRTF-A binding partners, we identified the putative histone lysine methyltransferase, PRDM6, and demonstrated that it was required for SMC differentiation. In overexpression experiments in COS-7 cells, we detected significant methylation on MRTF-A. Surprisingly, SMYD2 and SET7/9 strongly methylated MRTF-A, but PRDM6 did not. We found that SMDY2 methylated K27 within MRTF-A’s highly conserved basic nuclear localization signal. SMYD2-mediated methylation at K27 inhibited MRTF localization as well as MRTF-dependent activation of SMC transcription.
Advisors/Committee Members: Mangum, Kevin, Mack, Christopher P., Bautch, Victoria, Liu, Jiandong, Sethupathy, Praveen, Taylor, Joan.
Subjects/Keywords: School of Medicine; Department of Pathology and Laboratory Medicine
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Record Details
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Mangum, K. (2017). Genetic and Epigenetic Mechanisms Regulating Smooth Muscle Cell Differentiation. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:3e390865-999e-44be-b0f8-91bcda14f410
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):
Mangum, Kevin. “Genetic and Epigenetic Mechanisms Regulating Smooth Muscle Cell Differentiation.” 2017. Thesis, University of North Carolina. Accessed January 16, 2021.
https://cdr.lib.unc.edu/record/uuid:3e390865-999e-44be-b0f8-91bcda14f410.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Mangum, Kevin. “Genetic and Epigenetic Mechanisms Regulating Smooth Muscle Cell Differentiation.” 2017. Web. 16 Jan 2021.
Vancouver:
Mangum K. Genetic and Epigenetic Mechanisms Regulating Smooth Muscle Cell Differentiation. [Internet] [Thesis]. University of North Carolina; 2017. [cited 2021 Jan 16].
Available from: https://cdr.lib.unc.edu/record/uuid:3e390865-999e-44be-b0f8-91bcda14f410.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Mangum K. Genetic and Epigenetic Mechanisms Regulating Smooth Muscle Cell Differentiation. [Thesis]. University of North Carolina; 2017. Available from: https://cdr.lib.unc.edu/record/uuid:3e390865-999e-44be-b0f8-91bcda14f410
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
. 
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