{"id":{"repo_id":"iupui","oai_identifier":"oai:scholarworks.indianapolis.iu.edu:1805/5850"},"canonical_url":"https://search.dev.ndltd.org/etd/iupui/oai:scholarworks.indianapolis.iu.edu:1805/5850","repository":{"repo_id":"iupui","name":"IUPUI","base_url":"https://scholarworks.indianapolis.iu.edu/server/oai/request"},"display":{"title":"Myeloid cells induce neurofibromatosis type 1 aneurysm formation through inflammation and oxidative stress","abstract":"Neurofibromatosis Type 1 (NF1) is a genetic disorder resulting from mutations in the NF1 tumor suppressor gene. Neurofibromin is the protein product of NF1 and functions as a negative regulator of Ras activity in both hematopoietic and vascular wall cells, which are critical for maintaining blood vessel homeostasis. NF1 patients are predisposed to chronic inflammation and premature cardiovascular disease, including development of large arterial aneurysms, which may result in sudden death secondary to their rupture. However, the molecular pathogenesis of NF1 aneurysm formation is completely unknown. Utilizing a novel model of Nf1 murine aneurysm formation, we demonstrate that heterozygous inactivation of Nf1 (Nf1+/-) results in enhanced aneurysm formation with myeloid cell infiltration and increased reactive oxygen species in the vessel wall. Using cell lineage-restricted transgenic mice, we show that loss of a single Nf1 allele in myeloid cells is sufficient to recapitulate the Nf1+/- aneurysm phenotype in vivo. Additionally, oral administration of simvastatin, a statin with antioxidant and anti-inflammatory effects, significantly reduced aneurysm formation in Nf1+/- mice. Finally, the antioxidant apocynin was administered orally and also resulted in a significant reduction of Nf1+/- aneurysms. These data provide genetic and pharmacologic evidence that neurofibromin-deficient myeloid cells are the central cellular triggers for aneurysm formation in a novel model of NF1 vascular disease, implicated oxidative stress as the key biochemical mechanisms of NF1 aneurysm formation and provide a potential therapeutic target for NF1 vasculopathy.","abstract_html":"Neurofibromatosis Type 1 (NF1) is a genetic disorder resulting from mutations in the NF1 tumor suppressor gene. Neurofibromin is the protein product of NF1 and functions as a negative regulator of Ras activity in both hematopoietic and vascular wall cells, which are critical for maintaining blood vessel homeostasis. NF1 patients are predisposed to chronic inflammation and premature cardiovascular disease, including development of large arterial aneurysms, which may result in sudden death secondary to their rupture. However, the molecular pathogenesis of NF1 aneurysm formation is completely unknown. Utilizing a novel model of Nf1 murine aneurysm formation, we demonstrate that heterozygous inactivation of Nf1 (Nf1+/-) results in enhanced aneurysm formation with myeloid cell infiltration and increased reactive oxygen species in the vessel wall. Using cell lineage-restricted transgenic mice, we show that loss of a single Nf1 allele in myeloid cells is sufficient to recapitulate the Nf1+/- aneurysm phenotype in vivo. Additionally, oral administration of simvastatin, a statin with antioxidant and anti-inflammatory effects, significantly reduced aneurysm formation in Nf1+/- mice. Finally, the antioxidant apocynin was administered orally and also resulted in a significant reduction of Nf1+/- aneurysms. These data provide genetic and pharmacologic evidence that neurofibromin-deficient myeloid cells are the central cellular triggers for aneurysm formation in a novel model of NF1 vascular disease, implicated oxidative stress as the key biochemical mechanisms of NF1 aneurysm formation and provide a potential therapeutic target for NF1 vasculopathy.","abstract_has_math":false,"creators":["Downing, Brandon David"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Kapur, Reuben"],"committee_chairs":[],"committee_members":[],"year":2014,"date_issued":"2014-06","date_published":"2014-06","updated_at":"2026-07-24T02:41:52Z","subjects":["Cardiovascular Disease","Neurofibromatosis Type 1","Inflammation","Oxidative Stress","cre/lox","Murine Model","Aneurysm"],"languages":["en_US"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://dx.doi.org/10.7912/C2/1865"],"render_values":[{"text":"http://dx.doi.org/10.7912/C2/1865","href":"http://dx.doi.org/10.7912/C2/1865","code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/1805/5850","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Kapur, Reuben"]},{"key":"dc:contributor.other","label":"Dc Contributor Other","values":["Yoder, Mervin C.","Conway, Simon J.","Ingram Jr., David A."]},{"key":"dc:creator","label":"Author","values":["Downing, Brandon David"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2015-02-06T19:34:04Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2015-02-06T19:34:04Z"]},{"key":"dc:date.issued","label":"Date","values":["2014-06"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Cardiovascular Disease","Neurofibromatosis Type 1","Inflammation","Oxidative Stress","cre/lox","Murine Model","Aneurysm"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en_US"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/1805/5850","http://dx.doi.org/10.7912/C2/1865"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Indiana University-Purdue University Indianapolis (IUPUI)"]},{"key":"dc:description.abstract","label":"Abstract","values":["Neurofibromatosis Type 1 (NF1) is a genetic disorder resulting from mutations in the NF1 tumor suppressor gene. Neurofibromin is the protein product of NF1 and functions as a negative regulator of Ras activity in both hematopoietic and vascular wall cells, which are critical for maintaining blood vessel homeostasis. NF1 patients are predisposed to chronic inflammation and premature cardiovascular disease, including development of large arterial aneurysms, which may result in sudden death secondary to their rupture. However, the molecular pathogenesis of NF1 aneurysm formation is completely unknown. Utilizing a novel model of Nf1 murine aneurysm formation, we demonstrate that heterozygous inactivation of Nf1 (Nf1+/-) results in enhanced aneurysm formation with myeloid cell infiltration and increased reactive oxygen species in the vessel wall. Using cell lineage-restricted transgenic mice, we show that loss of a single Nf1 allele in myeloid cells is sufficient to recapitulate the Nf1+/- aneurysm phenotype in vivo. Additionally, oral administration of simvastatin, a statin with antioxidant and anti-inflammatory effects, significantly reduced aneurysm formation in Nf1+/- mice. Finally, the antioxidant apocynin was administered orally and also resulted in a significant reduction of Nf1+/- aneurysms. These data provide genetic and pharmacologic evidence that neurofibromin-deficient myeloid cells are the central cellular triggers for aneurysm formation in a novel model of NF1 vascular disease, implicated oxidative stress as the key biochemical mechanisms of NF1 aneurysm formation and provide a potential therapeutic target for NF1 vasculopathy."]},{"key":"dc:title","label":"Title","values":["Myeloid cells induce neurofibromatosis type 1 aneurysm formation through inflammation and oxidative stress"]}]}],"canonical_facts":{"dc:contributor.advisor":["Kapur, Reuben"],"dc:contributor.other":["Yoder, Mervin C.","Conway, Simon J.","Ingram Jr., David A."],"dc:creator":["Downing, Brandon David"],"dc:date.accessioned":["2015-02-06T19:34:04Z"],"dc:date.available":["2015-02-06T19:34:04Z"],"dc:date.issued":["2014-06"],"dc:description":["Indiana University-Purdue University Indianapolis (IUPUI)"],"dc:description.abstract":["Neurofibromatosis Type 1 (NF1) is a genetic disorder resulting from mutations in the NF1 tumor suppressor gene. Neurofibromin is the protein product of NF1 and functions as a negative regulator of Ras activity in both hematopoietic and vascular wall cells, which are critical for maintaining blood vessel homeostasis. NF1 patients are predisposed to chronic inflammation and premature cardiovascular disease, including development of large arterial aneurysms, which may result in sudden death secondary to their rupture. However, the molecular pathogenesis of NF1 aneurysm formation is completely unknown. Utilizing a novel model of Nf1 murine aneurysm formation, we demonstrate that heterozygous inactivation of Nf1 (Nf1+/-) results in enhanced aneurysm formation with myeloid cell infiltration and increased reactive oxygen species in the vessel wall. Using cell lineage-restricted transgenic mice, we show that loss of a single Nf1 allele in myeloid cells is sufficient to recapitulate the Nf1+/- aneurysm phenotype in vivo. Additionally, oral administration of simvastatin, a statin with antioxidant and anti-inflammatory effects, significantly reduced aneurysm formation in Nf1+/- mice. Finally, the antioxidant apocynin was administered orally and also resulted in a significant reduction of Nf1+/- aneurysms. These data provide genetic and pharmacologic evidence that neurofibromin-deficient myeloid cells are the central cellular triggers for aneurysm formation in a novel model of NF1 vascular disease, implicated oxidative stress as the key biochemical mechanisms of NF1 aneurysm formation and provide a potential therapeutic target for NF1 vasculopathy."],"dc:identifier.uri":["https://hdl.handle.net/1805/5850","http://dx.doi.org/10.7912/C2/1865"],"dc:language.iso":["en_US"],"dc:subject":["Cardiovascular Disease","Neurofibromatosis Type 1","Inflammation","Oxidative Stress","cre/lox","Murine Model","Aneurysm"],"dc:title":["Myeloid cells induce neurofibromatosis type 1 aneurysm formation through inflammation and oxidative stress"],"dc:type":["Thesis"]},"updated_at":"2026-07-24T02:41:52Z"}