{"id":14442,"date":"2024-05-23T07:59:56","date_gmt":"2024-05-23T07:59:56","guid":{"rendered":"https:\/\/www.nanion.de\/?post_type=resource_library&#038;p=14442"},"modified":"2024-05-23T07:59:56","modified_gmt":"2024-05-23T07:59:56","slug":"2024-susceptibility-to-innate-immune-activation-in-genetically-mediated-myocarditis","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/ja\/resource_library\/2024-susceptibility-to-innate-immune-activation-in-genetically-mediated-myocarditis\/","title":{"rendered":"2024 &#8211; Susceptibility to innate immune activation in genetically-mediated myocarditis"},"content":{"rendered":"<p>Myocarditis is clinically characterized by chest pain, arrhythmias, and heart failure, and treatment is often supportive. Mutations in DSP, a gene encoding the desmosomal protein<br \/>\ndesmoplakin, have been increasingly implicated in myocarditis. To model DSP-associated myocarditis and assess the role of innate immunity, we generated engineered heart tissues<br \/>\n(EHTs) using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with heterozygous DSP truncations (DSPtv) and a gene-edited homozygous deletion<br \/>\ncell line (DSP-\/-). At baseline, DSP-\/- EHTs displayed a transcriptomic signature of innate immune activation which was mirrored by cytokine release. Importantly, DSP-\/- EHTs were<br \/>\nhypersensitive to Toll-like receptor (TLR) stimulation demonstrating more contractile dysfunction compared to isogenic controls. Relative to DSP-\/- EHTs, heterozygous DSPtv EHTs had less functional impairment. DSPtv EHTs displayed heightened sensitivity to TLR stimulation, and when subjected to strain, DSPtv EHTs developed functional deficits indicating reduced<br \/>\ncontractile reserve compared to healthy control. Colchicine or NF\u03baB inhibitors improved strain-induced force deficits in DSPtv EHTs. Genomic correction of DSP p.R1951X using adenine<br \/>\nbase editing reduced inflammatory biomarker release from EHTs. Thus, EHTs replicate electrical and contractile phenotypes seen in human myocarditis implicating cytokine release as<br \/>\na key part of the myogenic susceptibility to inflammation. This heightened innate immune activation and sensitivity is a target for clinical intervention.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[34],"resource_type":[75],"application_areas":[53,77],"therapeutic_areas":[143],"target_categories":[],"target_families":[],"targets":[],"resource_keyword":[],"class_list":["post-14442","resource_library","type-resource_library","status-publish","hentry","products_tags-cardioexcyte-96","resource_type-publication","application_areas-assay-development-and-validation","application_areas-cell-ipscs-profiling","therapeutic_areas-assay-development-and-validation"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library\/14442","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/media?parent=14442"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/products_tags?post=14442"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_type?post=14442"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/application_areas?post=14442"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/therapeutic_areas?post=14442"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_categories?post=14442"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_families?post=14442"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/targets?post=14442"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_keyword?post=14442"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}