Von Hippel-Lindau Syndrome: Characterization of a Potentially Novel VEGF-A Isoform and Elucidation of Molecular and Vascular Mechanisms of Observed Phenotypic Changes

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dc.contributor.authorNorth, Morgan Hunteren
dc.contributor.committeechairChappell, John C.en
dc.contributor.committeememberHuckle, William R.en
dc.contributor.committeememberSmyth, James W.en
dc.contributor.departmentTranslational Biology, Medicine and Healthen
dc.date.accessioned2020-06-18T08:00:36Zen
dc.date.available2020-06-18T08:00:36Zen
dc.date.issued2020-06-17en
dc.description.abstractVon Hippel-Lindau (VHL) syndrome is an autosomal dominant predisposition to cancer in neurological tissues, the kidneys, adrenal glands, pancreas, and liver, including neurological hemangioblastoma (HB), pheochromocytoma (PCC), pancreatic neuroendocrine tumors (PNET), pancreatic and renal cysts, and clear cell renal cell carcinoma (ccRCC). The disease process follows Knudson's two-hit model, requiring spontaneous loss or mutation of a normal VHL tumor suppressor allele to induce expression of the disease. VHL syndrome principally involves dysregulation of oxygen sensing pathways including the Hypoxia Inducible Factor (HIF)-Vascular Endothelial Growth Factor-A (VEGF-A) and HIF-Erythropoietin (EPO) pathways. RNA sequencing (RNA-Seq) data from our previously published experiments revealed a potentially novel VEGF-A splice variant with excision of the VEGF Receptor-1 (VEGFR-1)/Flt-1 binding domain, rendering this isoform resistant to native down-regulation. Additionally, phenotypic changes were observed in adult VHL mutant mice, specifically very red appearing extremities with prominently visible vasculature. In order to determine the etiology of this phenotype, we observed red blood cell count, Epo gene expression levels, and arterialization of the blood vessels in these experimental mice as compared to littermate controls. Current research into the VEGF-A isoform is ongoing in the lab, and preliminary evidence for the etiology of the apparent chronic erythema phenotype is inconclusive due to lack of experimental replicates due to COVID-19 quarantine orders.en
dc.description.abstractgeneralVon Hippel-Lindau (VHL) syndrome is characterized by cancer development primarily in the brain and spinal cord, kidneys, adrenal glands, pancreas, and liver. VHL syndrome involves mutations which render the VHL gene dysfunctional. Since the VHL gene's normal role is one of preventing cancer development, sensing oxygen levels, and impacting blood vessel development, it follows that the loss of this gene results in tumor development with a rich blood vessel network. One of the downstream effectors of this process is a signaling molecule called Vascular Endothelial Growth Factor-A (VEGF-A). Our lab found a unique variant of VEGF-A, which may be overactive in the body in the setting of VHL disease. Additionally, we noted that our VHL mutant mice turned very red, and we sought to identify the biological cause of this phenomenon. In order to determine the cause of this redness, we studied red blood cell counts and their regulatory gene (Erythropoietin, EPO), as well as potential blood vessel abnormalities using high-power microscopy.en
dc.description.degreeMaster of Scienceen
dc.format.mediumETDen
dc.identifier.othervt_gsexam:26037en
dc.identifier.urihttp://hdl.handle.net/10919/99033en
dc.publisherVirginia Techen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectVon Hippel-Lindauen
dc.subjectVHLen
dc.subjectVascular Endothelial Growth Factoren
dc.subjectVEGFen
dc.subjectHypoxiaen
dc.subjectHypoxia Inducible Factor(s) HIF(s)en
dc.subjectNotchen
dc.subjectBlood Vesselsen
dc.subjectAngiogenesisen
dc.subjectTumorigenesisen
dc.titleVon Hippel-Lindau Syndrome: Characterization of a Potentially Novel VEGF-A Isoform and Elucidation of Molecular and Vascular Mechanisms of Observed Phenotypic Changesen
dc.typeThesisen
thesis.degree.disciplineTranslational Biology, Medicine, and Healthen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.levelmastersen
thesis.degree.nameMaster of Scienceen

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