{"id":{"repo_id":"ohiolink","oai_identifier":"oai:etd.ohiolink.edu:ucin1352485302"},"canonical_url":"https://search.dev.ndltd.org/etd/ohiolink/oai:etd.ohiolink.edu:ucin1352485302","repository":{"repo_id":"ohiolink","name":"OhioLINK","base_url":"https://etd.ohiolink.edu/acprod/odb_etd/ws/oai/oai"},"display":{"title":"BMPR2 and mTOR Signaling Pathways in Inflammatory Lung Diseases","abstract":"Inflammation occurs in many chronic lung diseases including pulmonary arterial hypertension (PAH) and asthma, however, the mechanisms underlying these diseases are not well understood. This thesis reports the findings from two studies that examined the role of the bone morphogenetic protein type II receptor (BMPR2) and the mammalian target of rapamycin (mTOR) signaling pathways in the pathogenesis of PAH and asthma, respectively. Previous studies have indicated mutations in BMPR2 as one of the contributing factors in the pathogenesis of the heritable form of PAH. Although BMPR2 mutations have been identified in patients with heritable PAH, disease penentrance is low, suggesting that environmental or other genetic factors may trigger symptomatic disease. One potential contributor is inflammation since inflammation has been associated with vascular remodeling and PAH in both patients and animal models, however, whether allergic inflammation could contribute to PAH in patients with BMPR2 mutations is unknown. Hence, the first project examined the role of allergic inflammation as a trigger/modifier of vascular remodeling and PAH in mice with deficient BMPR-II signaling. To address this question, we utilized mice which had reduced BMPR-II signaling and determined whether these mice would develop more severe vascular remodeling and PAH when exposed to chronic allergic inflammation. Wild-type and BMPR2 mutant mice were exposed to the allergen, house dust mite (HDM), for 7 or 20 weeks. Our studies showed similar increases in pulmonary arterial pressures and vascular remodeling in wild-type and BMPR2 mutant mice compared to controls. These data suggest that increases in pulmonary arterial remodeling and PAH triggered by allergic inflammation occurs despite reduced BMPR-II signaling. The second project examined the role of the mTOR signaling pathway in different stages of allergic asthma including initiation, progression, and after allergen re-exposure. The role of mTOR in T cell differentiation and other immune responses has been well studied, but the importance of this pathway in other key features of allergic asthma is poorly understood. Inhibition of mTOR, with the drug rapamycin, was used to assess the role of mTOR in acute and chronic models of allergic asthma. Rapamycin treatment, during the allergen sensitization period, prevented the initiation of allergic asthma including inhibition of allergen-induced IgE, airway hyperreactivity (AHR), inflammatory cells, and mucus-producing goblet cells. When rapamycin was administered after systemic sensitization, but just prior to allergen exposure to the lung, many key responses including increases in IgE, AHR, goblet cells, lung T cells, and IL-13 and leukotrienes were suppressed, although increases in inflammatory cells were not. In studies that assessed the role of mTOR after allergen re-exposure and during the progression towards chronic disease, rapamycin no longer attenuated AHR, inflammatory cell numbers, and cytokine levels, although IgE levels and T cell responses were still suppressed. These data demonstrate that mTOR signaling plays a critical role during the early stages of allergic asthma and while it contributes to disease progression and exacerbations, its role is more limited. This likely reflects the reported role of mTOR in early T cell activation and differentiation into specific effector T cell lineages.","abstract_html":"Inflammation occurs in many chronic lung diseases including pulmonary arterial hypertension (PAH) and asthma, however, the mechanisms underlying these diseases are not well understood. This thesis reports the findings from two studies that examined the role of the bone morphogenetic protein type II receptor (BMPR2) and the mammalian target of rapamycin (mTOR) signaling pathways in the pathogenesis of PAH and asthma, respectively. Previous studies have indicated mutations in BMPR2 as one of the contributing factors in the pathogenesis of the heritable form of PAH. Although BMPR2 mutations have been identified in patients with heritable PAH, disease penentrance is low, suggesting that environmental or other genetic factors may trigger symptomatic disease. One potential contributor is inflammation since inflammation has been associated with vascular remodeling and PAH in both patients and animal models, however, whether allergic inflammation could contribute to PAH in patients with BMPR2 mutations is unknown. Hence, the first project examined the role of allergic inflammation as a trigger/modifier of vascular remodeling and PAH in mice with deficient BMPR-II signaling. To address this question, we utilized mice which had reduced BMPR-II signaling and determined whether these mice would develop more severe vascular remodeling and PAH when exposed to chronic allergic inflammation. Wild-type and BMPR2 mutant mice were exposed to the allergen, house dust mite (HDM), for 7 or 20 weeks. Our studies showed similar increases in pulmonary arterial pressures and vascular remodeling in wild-type and BMPR2 mutant mice compared to controls. These data suggest that increases in pulmonary arterial remodeling and PAH triggered by allergic inflammation occurs despite reduced BMPR-II signaling. The second project examined the role of the mTOR signaling pathway in different stages of allergic asthma including initiation, progression, and after allergen re-exposure. The role of mTOR in T cell differentiation and other immune responses has been well studied, but the importance of this pathway in other key features of allergic asthma is poorly understood. Inhibition of mTOR, with the drug rapamycin, was used to assess the role of mTOR in acute and chronic models of allergic asthma. Rapamycin treatment, during the allergen sensitization period, prevented the initiation of allergic asthma including inhibition of allergen-induced IgE, airway hyperreactivity (AHR), inflammatory cells, and mucus-producing goblet cells. When rapamycin was administered after systemic sensitization, but just prior to allergen exposure to the lung, many key responses including increases in IgE, AHR, goblet cells, lung T cells, and IL-13 and leukotrienes were suppressed, although increases in inflammatory cells were not. In studies that assessed the role of mTOR after allergen re-exposure and during the progression towards chronic disease, rapamycin no longer attenuated AHR, inflammatory cell numbers, and cytokine levels, although IgE levels and T cell responses were still suppressed. These data demonstrate that mTOR signaling plays a critical role during the early stages of allergic asthma and while it contributes to disease progression and exacerbations, its role is more limited. This likely reflects the reported role of mTOR in early T cell activation and differentiation into specific effector T cell lineages.","abstract_has_math":false,"creators":["Mushaben, Elizabeth M."],"institution":"University of Cincinnati","degree_name":"PhD","degree_level":"doctoral","degree_discipline":"Medicine: Molecular and Developmental Biology","degree_department":null,"school":null,"contributors":["Lecras, Timothy"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2012,"date_issued":"2012","date_published":"2012","updated_at":"2026-07-24T03:36:23Z","subjects":["Molecular Biology","mTOR","BMPR2","asthma","pulmonary arterial hypertension","house dust mite","inflammation"],"languages":["English"],"rights":["unrestricted","This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws."],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://rave.ohiolink.edu/etdc/view?acc_num=ucin1352485302","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Lecras, Timothy"]},{"key":"dc:creator","label":"Author","values":["Mushaben, Elizabeth M."]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2012"]},{"key":"dc:publisher","label":"Institution","values":["University of Cincinnati / OhioLINK"]},{"key":"dc:type","label":"Dc Type","values":["Electronic Thesis or Dissertation"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Medicine: Molecular and Developmental Biology"]},{"key":"thesis:degree_level","label":"Degree Level","values":["doctoral"]},{"key":"thesis:degree_name","label":"Degree Name","values":["PhD"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Cincinnati"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Molecular Biology","mTOR","BMPR2","asthma","pulmonary arterial hypertension","house dust mite","inflammation"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["English"]},{"key":"dc:rights","label":"Dc Rights","values":["unrestricted","This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws."]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://rave.ohiolink.edu/etdc/view?acc_num=ucin1352485302"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Inflammation occurs in many chronic lung diseases including pulmonary arterial hypertension (PAH) and asthma, however, the mechanisms underlying these diseases are not well understood. This thesis reports the findings from two studies that examined the role of the bone morphogenetic protein type II receptor (BMPR2) and the mammalian target of rapamycin (mTOR) signaling pathways in the pathogenesis of PAH and asthma, respectively. Previous studies have indicated mutations in BMPR2 as one of the contributing factors in the pathogenesis of the heritable form of PAH. Although BMPR2 mutations have been identified in patients with heritable PAH, disease penentrance is low, suggesting that environmental or other genetic factors may trigger symptomatic disease. One potential contributor is inflammation since inflammation has been associated with vascular remodeling and PAH in both patients and animal models, however, whether allergic inflammation could contribute to PAH in patients with BMPR2 mutations is unknown. Hence, the first project examined the role of allergic inflammation as a trigger/modifier of vascular remodeling and PAH in mice with deficient BMPR-II signaling. To address this question, we utilized mice which had reduced BMPR-II signaling and determined whether these mice would develop more severe vascular remodeling and PAH when exposed to chronic allergic inflammation. Wild-type and BMPR2 mutant mice were exposed to the allergen, house dust mite (HDM), for 7 or 20 weeks. Our studies showed similar increases in pulmonary arterial pressures and vascular remodeling in wild-type and BMPR2 mutant mice compared to controls. These data suggest that increases in pulmonary arterial remodeling and PAH triggered by allergic inflammation occurs despite reduced BMPR-II signaling. The second project examined the role of the mTOR signaling pathway in different stages of allergic asthma including initiation, progression, and after allergen re-exposure. The role of mTOR in T cell differentiation and other immune responses has been well studied, but the importance of this pathway in other key features of allergic asthma is poorly understood. Inhibition of mTOR, with the drug rapamycin, was used to assess the role of mTOR in acute and chronic models of allergic asthma. Rapamycin treatment, during the allergen sensitization period, prevented the initiation of allergic asthma including inhibition of allergen-induced IgE, airway hyperreactivity (AHR), inflammatory cells, and mucus-producing goblet cells. When rapamycin was administered after systemic sensitization, but just prior to allergen exposure to the lung, many key responses including increases in IgE, AHR, goblet cells, lung T cells, and IL-13 and leukotrienes were suppressed, although increases in inflammatory cells were not. In studies that assessed the role of mTOR after allergen re-exposure and during the progression towards chronic disease, rapamycin no longer attenuated AHR, inflammatory cell numbers, and cytokine levels, although IgE levels and T cell responses were still suppressed. These data demonstrate that mTOR signaling plays a critical role during the early stages of allergic asthma and while it contributes to disease progression and exacerbations, its role is more limited. This likely reflects the reported role of mTOR in early T cell activation and differentiation into specific effector T cell lineages."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf","p.170","25.89 MB"]},{"key":"dc:title","label":"Title","values":["BMPR2 and mTOR Signaling Pathways in Inflammatory Lung Diseases"]}]}],"canonical_facts":{"dc:contributor":["Lecras, Timothy"],"dc:creator":["Mushaben, Elizabeth M."],"dc:date":["2012"],"dc:description":["Inflammation occurs in many chronic lung diseases including pulmonary arterial hypertension (PAH) and asthma, however, the mechanisms underlying these diseases are not well understood. This thesis reports the findings from two studies that examined the role of the bone morphogenetic protein type II receptor (BMPR2) and the mammalian target of rapamycin (mTOR) signaling pathways in the pathogenesis of PAH and asthma, respectively. Previous studies have indicated mutations in BMPR2 as one of the contributing factors in the pathogenesis of the heritable form of PAH. Although BMPR2 mutations have been identified in patients with heritable PAH, disease penentrance is low, suggesting that environmental or other genetic factors may trigger symptomatic disease. One potential contributor is inflammation since inflammation has been associated with vascular remodeling and PAH in both patients and animal models, however, whether allergic inflammation could contribute to PAH in patients with BMPR2 mutations is unknown. Hence, the first project examined the role of allergic inflammation as a trigger/modifier of vascular remodeling and PAH in mice with deficient BMPR-II signaling. To address this question, we utilized mice which had reduced BMPR-II signaling and determined whether these mice would develop more severe vascular remodeling and PAH when exposed to chronic allergic inflammation. Wild-type and BMPR2 mutant mice were exposed to the allergen, house dust mite (HDM), for 7 or 20 weeks. Our studies showed similar increases in pulmonary arterial pressures and vascular remodeling in wild-type and BMPR2 mutant mice compared to controls. These data suggest that increases in pulmonary arterial remodeling and PAH triggered by allergic inflammation occurs despite reduced BMPR-II signaling. The second project examined the role of the mTOR signaling pathway in different stages of allergic asthma including initiation, progression, and after allergen re-exposure. The role of mTOR in T cell differentiation and other immune responses has been well studied, but the importance of this pathway in other key features of allergic asthma is poorly understood. Inhibition of mTOR, with the drug rapamycin, was used to assess the role of mTOR in acute and chronic models of allergic asthma. Rapamycin treatment, during the allergen sensitization period, prevented the initiation of allergic asthma including inhibition of allergen-induced IgE, airway hyperreactivity (AHR), inflammatory cells, and mucus-producing goblet cells. When rapamycin was administered after systemic sensitization, but just prior to allergen exposure to the lung, many key responses including increases in IgE, AHR, goblet cells, lung T cells, and IL-13 and leukotrienes were suppressed, although increases in inflammatory cells were not. In studies that assessed the role of mTOR after allergen re-exposure and during the progression towards chronic disease, rapamycin no longer attenuated AHR, inflammatory cell numbers, and cytokine levels, although IgE levels and T cell responses were still suppressed. These data demonstrate that mTOR signaling plays a critical role during the early stages of allergic asthma and while it contributes to disease progression and exacerbations, its role is more limited. This likely reflects the reported role of mTOR in early T cell activation and differentiation into specific effector T cell lineages."],"dc:format":["application/pdf","p.170","25.89 MB"],"dc:identifier":["http://rave.ohiolink.edu/etdc/view?acc_num=ucin1352485302"],"dc:language":["English"],"dc:publisher":["University of Cincinnati / OhioLINK"],"dc:rights":["unrestricted","This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws."],"dc:subject":["Molecular Biology","mTOR","BMPR2","asthma","pulmonary arterial hypertension","house dust mite","inflammation"],"dc:title":["BMPR2 and mTOR Signaling Pathways in Inflammatory Lung Diseases"],"dc:type":["Electronic Thesis or Dissertation"],"thesis:degree_discipline":["Medicine: Molecular and Developmental Biology"],"thesis:degree_level":["doctoral"],"thesis:degree_name":["PhD"],"thesis:institution_name":["University of Cincinnati"]},"updated_at":"2026-07-24T03:36:23Z"}