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University of North Carolina
1.
Wang, Shiliang.
Dissecting the Genetic Architecture of Complex Traits: Hot Spots and Vascular Collaterals.
Degree: Cell Biology and Physiology, 2011, University of North Carolina
URL: https://cdr.lib.unc.edu/record/uuid:5bb885d6-0e65-4c7e-b100-3d11579eb552 
► Collateral arteries are endogenous “bypass vessels” that minimize tissue injury during arterial obstruction. Recent studies from our laboratory demonstrate that wide variation exists among individuals…
(more)
▼ Collateral arteries are endogenous “bypass vessels” that minimize tissue injury during arterial obstruction. Recent studies from our laboratory demonstrate that wide variation exists among individuals in the extent (number and diameter) of native (pre-existing) collaterals in healthy tissue and their outward remodeling (increase in anatomic diameter) in obstructive disease. Evidence suggests this variation contributes importantly to the wide variation in thromboembolic stroke, ischemic heart disease and peripheral arterial disease in humans. We hypothesized that genetic components contribute significantly to this variation. We tested this hypothesis in 243 C57BL/6 X BALB/c (CXB) F2 mice, wherein number and diameter of native cerebral collaterals and collateral remodeling after middle cerebral artery occlusion (MCAO) were measured. Linkage analysis identified a major QTL on chromosome 7 (Canq1) responsible for more than 30% of the variation in collateral extent. Three additional QTL were obtained for collateral number. Analysis of chromosome substitution and CXB recombinant inbred strains confirmed the dominant role of the Canq1 locus. We also identified a QTL on chromosome 11 linked to variation in collateral remodeling. Efficient mix model association mapping (EMMA) of collateral number among 15 inbred strains delineated
172k (p=0.00002) and 290k (p=0.0004) base-pair regions containing 2 and 7 candidate genes, respectively, within Canq1. Analysis of six additional inbred strains, chosen according to their haplotype within the 172 kb EMMA region, strengthened and narrowed the locus from 172 kb interval to 2 kb. In candidate gene analyses, we found that collateral extent, infarct volume after MCAO, bleeding and re-bleeding times did not differ between Itgal-/,-IL4-/- or IL4-receptor-α-/- and wildtype mice. mRNA expression of 120 genes within the 95% confidence interval of Canq1, measured in the pial vasculature of C57BL/6 and BALB/c at embryonic day-14.5, -16.5 and -18.5 when the collateral circulation forms, identified 19 differentially expressed genes.
These results demonstrate that native collateral extent and collateral remodeling are heritable complex traits, with a highly significant QTL on chromosome 7 governing the majority of the variation in these traits. Furthermore, my work prioritizes a set of genes for future analysis as candidates underlying the process of collateral formation and its variation among individuals.
Advisors/Committee Members: Wang, Shiliang, Faber, James.
Subjects/Keywords: School of Medicine; Department of Cell Biology and Physiology
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APA (6th Edition):
Wang, S. (2011). Dissecting the Genetic Architecture of Complex Traits: Hot Spots and Vascular Collaterals. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:5bb885d6-0e65-4c7e-b100-3d11579eb552
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):
Wang, Shiliang. “Dissecting the Genetic Architecture of Complex Traits: Hot Spots and Vascular Collaterals.” 2011. Thesis, University of North Carolina. Accessed January 16, 2021.
https://cdr.lib.unc.edu/record/uuid:5bb885d6-0e65-4c7e-b100-3d11579eb552.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Wang, Shiliang. “Dissecting the Genetic Architecture of Complex Traits: Hot Spots and Vascular Collaterals.” 2011. Web. 16 Jan 2021.
Vancouver:
Wang S. Dissecting the Genetic Architecture of Complex Traits: Hot Spots and Vascular Collaterals. [Internet] [Thesis]. University of North Carolina; 2011. [cited 2021 Jan 16].
Available from: https://cdr.lib.unc.edu/record/uuid:5bb885d6-0e65-4c7e-b100-3d11579eb552.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Wang S. Dissecting the Genetic Architecture of Complex Traits: Hot Spots and Vascular Collaterals. [Thesis]. University of North Carolina; 2011. Available from: https://cdr.lib.unc.edu/record/uuid:5bb885d6-0e65-4c7e-b100-3d11579eb552
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of North Carolina
2.
Klein, Klara.
Adrenomedullin, Chemokine Receptors, and Receptor Activity Modifying Proteins in Lymphangiogenesis.
Degree: Cell Biology and Physiology, 2015, University of North Carolina
URL: https://cdr.lib.unc.edu/record/uuid:ef2c8a24-597a-4c0d-9642-2850b8f8557e
► Over the past decade, we have begun to appreciate that the lymphatic vascular system does more than simply return plasma back into the circulatory system…
(more)
▼ Over the past decade, we have begun to appreciate that the lymphatic vascular system does more than simply return plasma back into the circulatory system and, in fact, contributes to a wide variety of normal and disease states. For this reason, much research has been devoted to understanding how lymphatic vessels form and function, with a particular interest in which molecules contribute to lymphatic vessel growth and maintenance. Here, we have focused on a potent lymphangiogenic factor, adrenomedullin, and its known roles in lymphangiogenesis, lymphatic function, and lymphatic disease. In the course of our studies, we have discovered that the decoy receptor CXCR7 is required as a molecular rheostat for controlling the concentration of AM ligand during cardiac and lymphatic vascular development. Loss of mammalian CXCR7 results in postnatal lethality due to aberrant cardiac development and myocyte hyperplasia. In Part I, we provide the molecular underpinning for this proliferative phenotype by demonstrating that the dosage and signaling of adrenomedullin is tightly controlled by CXCR7. To this end, Cxcr7-/- mice exhibit gain-of-function cardiac and lymphatic vascular phenotypes which can be reversed upon genetic depletion of adrenomedullin ligand. In addition to identifying a biological ligand accountable for the phenotypes of Cxcr7-/- mice, these results reveal a previously underappreciated role for decoy receptors as molecular rheostats in controlling the timing and extent of GPCR-mediated cardiovascular development. In Part II, we investigated whether CXCR7 and related chemokine receptors (CKRs), CXCR4 and CCR5, form protein-protein interactions with one component of the AM signaling system, Receptor Activity Modifying Proteins (RAMPs). BRET studies, confocal microscopy, and fluorogen-activating protein assays indicate CKRs associate with RAMP2 and RAMP3 in vitro, suggesting that a broader group of GPCRs interact with RAMPs than previously thought. Future studies will allow us to characterize the breadth of RAMP interactions, facilitating a shift in the focus of RAMP research to the design of functional assays that help determine whether a given GPCR-RAMP association affects biological activity. A thorough understanding of RAMP effects on biology has the potential to have significant clinical impact, as targeting of the RAMP-GPCR interface could yield specific, high affinity drugs.
Advisors/Committee Members: Klein, Klara, Caron, Klara, Faber, James, Tarrant, Teresa, Bautch, Victoria, Dudley, Andrew.
Subjects/Keywords: Physiology; Biology; Molecular biology; School of Medicine; Department of Cell Biology and Physiology
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APA (6th Edition):
Klein, K. (2015). Adrenomedullin, Chemokine Receptors, and Receptor Activity Modifying Proteins in Lymphangiogenesis. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:ef2c8a24-597a-4c0d-9642-2850b8f8557e
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):
Klein, Klara. “Adrenomedullin, Chemokine Receptors, and Receptor Activity Modifying Proteins in Lymphangiogenesis.” 2015. Thesis, University of North Carolina. Accessed January 16, 2021.
https://cdr.lib.unc.edu/record/uuid:ef2c8a24-597a-4c0d-9642-2850b8f8557e.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Klein, Klara. “Adrenomedullin, Chemokine Receptors, and Receptor Activity Modifying Proteins in Lymphangiogenesis.” 2015. Web. 16 Jan 2021.
Vancouver:
Klein K. Adrenomedullin, Chemokine Receptors, and Receptor Activity Modifying Proteins in Lymphangiogenesis. [Internet] [Thesis]. University of North Carolina; 2015. [cited 2021 Jan 16].
Available from: https://cdr.lib.unc.edu/record/uuid:ef2c8a24-597a-4c0d-9642-2850b8f8557e.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Klein K. Adrenomedullin, Chemokine Receptors, and Receptor Activity Modifying Proteins in Lymphangiogenesis. [Thesis]. University of North Carolina; 2015. Available from: https://cdr.lib.unc.edu/record/uuid:ef2c8a24-597a-4c0d-9642-2850b8f8557e
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of North Carolina
3.
Dunleavey, James.
PECAM-1-DEPENDENT VASCULAR MIMICRY IN MELANOMA: CONTRIBUTIONS TO ANTI-ANGIOGENIC RESISTANCE.
Degree: Cell Biology and Physiology, 2016, University of North Carolina
URL: https://cdr.lib.unc.edu/record/uuid:cab5d7bc-9082-401f-95d7-c632f7cd1027
► The development of a perfused blood vasculature is a requirement both in development and for many human pathologies. Critically, the formation of new blood vessels…
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▼ The development of a perfused blood vasculature is a requirement both in development and for many human pathologies. Critically, the formation of new blood vessels through angiogenesis has been identified as a hallmark of cancer progression. A major effort has been undertaken to target the blood vessels of nascent and metastatic tumors to inhibit tumor growth. Therapies targeting the blood vasculature have shown limited efficacy, and multiple modes or resistance have been proposed. While attempting to characterize endothelial cells from mouse models of melanoma, we discovered a novel subpopulation of tumor cells expressing the endothelial cell marker PECAM-1. PECAM-1+ melanoma participate in a tumor cell derived vasculature in a form of vasculogenic mimicry (VM). PECAM-1+ tumor cells form PECAM-1- dependent vascular-like networks in vitro and generate perfused vascular networks in vivo in a VEGF-independent fashion. Transcriptional activator AP-2a is diminished in PECAM-1+ melanoma and represses PECAM-1 expression. Re-expression of AP-2a in PECAM-1+ tumor cells blocks PECAM-1 expression and inhibits tube-forming ability, and knockdown of AP-2a upregulates PECAM-1 in PECAM-1- tumor cells. We identified PECAM-1+ tumor cells in both murine and human melanoma, and propose that PECAM-1+ melanoma cells may instigate VM, collaborate with host endothelial cells, and form PECAM-1-dependent vascular channels which are refractory to VEGF inhibition.
Advisors/Committee Members: Dunleavey, James, Dudley, Andrew, Faber, James, Bautch, Victoria, Thomas, Nancy, Tzima, Eleni.
Subjects/Keywords: School of Medicine; Department of Cell Biology and Physiology
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APA ·
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APA (6th Edition):
Dunleavey, J. (2016). PECAM-1-DEPENDENT VASCULAR MIMICRY IN MELANOMA: CONTRIBUTIONS TO ANTI-ANGIOGENIC RESISTANCE. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:cab5d7bc-9082-401f-95d7-c632f7cd1027
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):
Dunleavey, James. “PECAM-1-DEPENDENT VASCULAR MIMICRY IN MELANOMA: CONTRIBUTIONS TO ANTI-ANGIOGENIC RESISTANCE.” 2016. Thesis, University of North Carolina. Accessed January 16, 2021.
https://cdr.lib.unc.edu/record/uuid:cab5d7bc-9082-401f-95d7-c632f7cd1027.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Dunleavey, James. “PECAM-1-DEPENDENT VASCULAR MIMICRY IN MELANOMA: CONTRIBUTIONS TO ANTI-ANGIOGENIC RESISTANCE.” 2016. Web. 16 Jan 2021.
Vancouver:
Dunleavey J. PECAM-1-DEPENDENT VASCULAR MIMICRY IN MELANOMA: CONTRIBUTIONS TO ANTI-ANGIOGENIC RESISTANCE. [Internet] [Thesis]. University of North Carolina; 2016. [cited 2021 Jan 16].
Available from: https://cdr.lib.unc.edu/record/uuid:cab5d7bc-9082-401f-95d7-c632f7cd1027.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Dunleavey J. PECAM-1-DEPENDENT VASCULAR MIMICRY IN MELANOMA: CONTRIBUTIONS TO ANTI-ANGIOGENIC RESISTANCE. [Thesis]. University of North Carolina; 2016. Available from: https://cdr.lib.unc.edu/record/uuid:cab5d7bc-9082-401f-95d7-c632f7cd1027
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of North Carolina
4.
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 ·
Chicago ·
MLA ·
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Export
to Zotero / EndNote / Reference
Manager
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
5.
Clayton, Jason Allen.
Role of vascular endothelial growth factor-A in collateral growth and development.
Degree: Cell Biology and Physiology, 2008, University of North Carolina
URL: https://cdr.lib.unc.edu/record/uuid:a7117723-4049-4238-b482-092cc79efb93
► Ischemic vascular disease is the leading cause of morbidity and mortality in the United States. Current therapies rely on invasive surgical procedures. Arteriogenesis, or collateral…
(more)
▼ Ischemic vascular disease is the leading cause of morbidity and mortality in the United States. Current therapies rely on invasive surgical procedures. Arteriogenesis, or collateral artery growth, has the potential to greatly improve the outcome of patients with ischemic vascular disease by providing an endogenous bypass circulation. However, the underlying biology of arteriogenesis remains poorly understood. There are conflicting animal and clinical reports of VEGF administration improving outcomes or increasing adverse effects. Because of systemic VEGF's pleiotropic functions, we hypothesized that local endogenous VEGF directly promotes the growth of collaterals. In addition, because of its role in vascular branching morphogenesis we hypothesized that VEGF may also play a role in the embryonic development of collaterals. To test these hypotheses, we used mouse models genetically targeting the VEGF pathway (VEGFhi/+, VEGFlo/+, VEGFR-1+/-, and VEGFR-2+/-) and local inhibitory approaches combining plasmid electroporation of Cre recombinase in VEGFloxP/loxP mice and FltIgG (VEGF-trap) in wild-type mice. We have found that VEGFR-1 is the principle VEGF receptor responsible for mediating arteriogenesis through recruitment of circulating monocytes. We also found impaired arteriogenesis in mice genetically expressing low levels of VEGF (VEGFlo/+). In addition, Cre-mediated deletion of VEGF in the adductor led to impaired plantar perfusion recovery, increased ischemic appearance, and impaired limb use. Expression of FltIgG in the adductor also increased ischemic appearance and impaired limb use. There was also evidence of impaired collateral perfusion despite normal plantar perfusion. We found a VEGF genotype - collateral density relationship, such that VEGFhi/+ mice had greater collaterals while VEGFlo/+ mice had fewer. Developmentally, we found that VEGFhi/+ and wild-type mice were born with more collaterals than VEGFlo/+. Interestingly in wild-type and VEGFlo/+ mice collateral density declined over the first 3 weeks of life at which time the adult density was attained, while VEGFhi/+ mice retained their collaterals from birth. These data suggest that VEGF levels must be maintained high enough to establish optimal collateral density and to ensure maturation of nascent collaterals during development. We identified a key role for VEGFR-1 in mediating collateral enlargement in ischemia. In addition, we have identified the first molecule, VEGF, responsible for the formation of native collaterals in healthy tissue.
Advisors/Committee Members: Clayton, Jason Allen, Faber, James.
Subjects/Keywords: School of Medicine; Department of Cell Biology and Physiology
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APA ·
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MLA ·
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to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Clayton, J. A. (2008). Role of vascular endothelial growth factor-A in collateral growth and development. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:a7117723-4049-4238-b482-092cc79efb93
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):
Clayton, Jason Allen. “Role of vascular endothelial growth factor-A in collateral growth and development.” 2008. Thesis, University of North Carolina. Accessed January 16, 2021.
https://cdr.lib.unc.edu/record/uuid:a7117723-4049-4238-b482-092cc79efb93.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Clayton, Jason Allen. “Role of vascular endothelial growth factor-A in collateral growth and development.” 2008. Web. 16 Jan 2021.
Vancouver:
Clayton JA. Role of vascular endothelial growth factor-A in collateral growth and development. [Internet] [Thesis]. University of North Carolina; 2008. [cited 2021 Jan 16].
Available from: https://cdr.lib.unc.edu/record/uuid:a7117723-4049-4238-b482-092cc79efb93.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Clayton JA. Role of vascular endothelial growth factor-A in collateral growth and development. [Thesis]. University of North Carolina; 2008. Available from: https://cdr.lib.unc.edu/record/uuid:a7117723-4049-4238-b482-092cc79efb93
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
. 
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