{"response":{"docs":[{"system_create_dtsi":"2017-10-27T02:31:18Z","system_modified_dtsi":"2018-08-01T18:36:54Z","has_model_ssim":["Article"],"id":"bc386t07f","accessControl_ssim":["199961fe-7545-4e66-987e-4522e8c9138e"],"hasRelatedMediaFragment_ssim":["bc386t08q"],"hasRelatedImage_ssim":["bc386t08q"],"depositor_ssim":["cancelje@ucmail.uc.edu"],"depositor_tesim":["cancelje@ucmail.uc.edu"],"title_tesim":["Pathogenesis of ELANE-Mutant Severe Neutropenia Revealed by Induced Pluripotent Stem Cells"],"date_uploaded_dtsi":"2017-02-08T00:00:00Z","date_modified_dtsi":"2017-04-10T00:00:00Z","isPartOf_ssim":["admin_set/default"],"proxy_depositor_ssim":["peckjd@mail.uc.edu"],"journal_title_tesim":["Pathogenesis of ELANE-mutant severe neutropenia revealed by induced pluripotent stem cells"],"college_tesim":["Medicine"],"department_tesim":["Hoxworth Blood Center"],"note_tesim":["This work was part of a pilot \"mediated-deposit model\" where library staff found potential works, later submitted for faculty review"],"creator_tesim":["Lutzko, C.","Mehta, P.","Kalfa, T.","Aronow, B. J.","Myers, K.","Grimes, H. L.","Horwitz, M.","Cancelas, Jose A.","Valencia, C. A.","Trump, L.","Nayak, R. C."],"publisher_tesim":["The Journal of Clinical Investigation"],"description_tesim":["Severe congenital neutropenia (SCN) is often associated with inherited heterozygous point mutations in ELANE, which\nencodes neutrophil elastase (NE). However, a lack of appropriate models to recapitulate SCN has substantially hampered\nthe understanding of the genetic etiology and pathobiology of this disease. To this end, we generated both normal and SCN\npatient–derived induced pluripotent stem cells (iPSCs), and performed genome editing and differentiation protocols that\nrecapitulate the major features of granulopoiesis. Pathogenesis of ELANE point mutations was the result of promyelocyte\ndeath and differentiation arrest, and was associated with NE mislocalization and activation of the unfolded protein\nresponse/ER stress (UPR/ER stress). Similarly, high-dose G-CSF (or downstream signaling through AKT/BCL2) rescues\nthe dysgranulopoietic defect in SCN patient–derived iPSCs through C/EBPβ-dependent emergency granulopoiesis. In\ncontrast, sivelestat, an NE-specific small-molecule inhibitor, corrected dysgranulopoiesis by restoring normal intracellular\nNE localization in primary granules; ameliorating UPR/ER stress; increasing expression of CEBPA, but not CEBPB; and\npromoting promyelocyte survival and differentiation. Together, these data suggest that SCN disease pathogenesis includes\nNE mislocalization, which in turn triggers dysfunctional survival signaling and UPR/ER stress. This paradigm has the\npotential to be clinically exploited to achieve therapeutic responses using lower doses of G-CSF combined with targeting to\ncorrect NE mislocalization."],"license_tesim":["http://rightsstatements.org/vocab/InC/1.0/"],"date_created_tesim":["2015-07"],"source_tesim":["Pathogenesis of ELANE-mutant severe neutropenia revealed by induced pluripotent stem cells"],"thumbnail_path_ss":"/downloads/bc386t08q?file=thumbnail","suppressed_bsi":false,"actionable_workflow_roles_ssim":["admin_set/default-default-depositing"],"workflow_state_name_ssim":["deposited"],"member_ids_ssim":["bc386t08q"],"file_set_ids_ssim":["bc386t08q"],"visibility_ssi":"open","admin_set_tesim":["Default Admin Set"],"sort_title_ssi":"PATHOGENESIS OF ELANEMUTANT SEVERE NEUTROPENIA REVEALED BY INDUCED PLURIPOTENT STEM CELLS","human_readable_type_tesim":["Article"],"read_access_group_ssim":["public"],"edit_access_person_ssim":["cancelje@ucmail.uc.edu"],"nesting_collection__pathnames_ssim":["bc386t07f"],"nesting_collection__deepest_nested_depth_isi":1,"_version_":1697079758815232000,"timestamp":"2021-04-15T04:36:18.875Z","score":0.00049999997}],"facets":[{"name":"human_readable_type_sim","items":[{"value":"Article","hits":1,"label":"Article"}],"label":"Human Readable Type Sim"},{"name":"creator_sim","items":[{"value":"Aronow, B. 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