{"id":7,"date":"2020-02-16T14:58:58","date_gmt":"2020-02-16T22:58:58","guid":{"rendered":"http:\/\/labs.wsu.edu\/chenglab\/?page_id=7"},"modified":"2022-01-31T19:39:10","modified_gmt":"2022-02-01T03:39:10","slug":"research","status":"publish","type":"page","link":"https:\/\/labs.wsu.edu\/chenglab\/research\/","title":{"rendered":"Research"},"content":{"rendered":"
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Developing New Treatments for Heart Disease<\/strong><\/p>\n

Heart disease, the leading cause of death in the United States, is frequently associated with cardiac cell death. Understanding the cell death mechanisms could uncover new drug targets for heart protection.<\/p>\n

Adult Mouse Cardiomyocytes (AMCMs)<\/p>\n

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The long-term research goals<\/strong> of the Cheng lab are to identify novel molecules involved in the regulation of cardiac cell death, including apoptosis, necrosis, and autophagy-dependent cell death. We use biochemical, molecular, cellular, genetic, pathophysiological and histological approaches, to study many types of cardiovascular disorders. Specifically, we are interested in cancer treatment-related cardiotoxicity, myocardial infarction, ischemia\/reperfusion injury, cardiac hypertrophy and heart failure. Our ultimate purpose is to develop new treatments for heart disease.<\/p>\n<\/p><\/div>\n<\/section>\n

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Adult Mouse Heart Sections<\/p>\n

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Neonatal Rat Cardiomyocytes (NRCMs, red<\/em>) and Cardiac Fibroblasts (green<\/em>)<\/p>\n

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Understanding How Cancer Treatment Damages the Heart
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The anthracycline compounds, widely used in current cancer chemotherapy, can cause irreversible, dose-dependent cardiac injury including cardiomyocyte apoptosis and cardiac atrophy. We show that the anthracycline doxorubicin induces CDK2-dependent FOXO1 activation, which is necessary for both apoptosis and atrophy. Moreover, we identify FOXO1 as a transcription factor for the pro-apoptotic gene Bim and the pro-atrophic gene MuRF1. Using a small molecule FOXO1 inhibitor AS1842856, we show that pharmacological inhibition of FOXO1 attenuates doxorubicin-induced systolic dysfunction, cardiac atrophy, and ventricular remodeling. Our findings, for the first time, establish FOXO1 as a critical mediator of doxorubicin-induced cardiotoxicity. Our study identifies FOXO1 as a potential drug target in anthracycline cardiotoxicity. Small molecule FOXO1 inhibitors, which are currently under clinical development, could represent promising therapeutics for cardiomyopathy and heart failure caused by cancer chemotherapy.<\/p>\n

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Improving Treatment for Heart Attack<\/strong><\/p>\n

Reperfusion therapy, the standard treatment for acute myocardial infarction (i.e. heart attack), can trigger necrotic death of cardiomyocytes and provoke ischemia\/reperfusion (I\/R) injury. However, signaling pathways that regulate cardiomyocyte necrosis remain largely unknown. Our recent genome-wide RNAi screen has identified a potential necrosis suppressor gene PRKAR1A<\/em>, which encodes PKA regulatory subunit 1\u03b1 (R1\u03b1). R1\u03b1 is primarily known for regulating PKA activity by sequestering PKA catalytic subunits in the absence of cAMP. Here, we showed that depletion of R1\u03b1 augmented cardiomyocyte necrosis in vitro<\/em> and in vivo<\/em>, resulting in exaggerated myocardial I\/R injury and contractile dysfunction. Mechanistically, R1\u03b1 loss downregulated the Nrf2 antioxidant transcription factor and aggravated oxidative stress following I\/R. Degradation of the endogenous Nrf2 inhibitor Keap1 through p62-dependent selective autophagy was blocked by R1\u03b1 depletion. Phosphorylation of p62 at Ser349 by mammalian target of rapamycin complex 1 (mTORC1), a critical step in p62-Keap1 interaction, was induced by I\/R, but diminished by R1\u03b1 loss. Activation of PKA by forskolin or isoproterenol almost completely abolished hydrogen-peroxide-induced p62 phosphorylation. In conclusion, R1\u03b1 loss induces unrestrained PKA activation and impairs the mTORC1-p62-Keap1-Nrf2 antioxidant defense system, leading to aggravated oxidative stress, necrosis, and myocardial I\/R injury. Our findings uncover a novel role of PKA in oxidative stress and necrosis, which may be exploited to develop new cardioprotective therapies.<\/p>\n

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Developing New Treatments for Heart Disease<\/strong><\/p>\n

Heart disease, the leading cause of death in the United States, is frequently associated with cardiac cell death. Understanding the cell death mechanisms could uncover new drug targets for heart protection.<\/p>\n

Adult Mouse Cardiomyocytes (AMCMs)<\/p>\n

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The long-term research goals<\/strong> of the Cheng lab are to identify novel molecules involved in the regulation of cardiac cell death, including apoptosis, necrosis, and autophagy-dependent cell death. We use biochemical, molecular, cellular, genetic, pathophysiological … » More …<\/span><\/a><\/p>\n","protected":false},"author":17550,"featured_media":0,"parent":0,"menu_order":2,"comment_status":"closed","ping_status":"closed","template":"template-builder.php","meta":[],"wsuwp_university_location":[],"wsuwp_university_org":[],"_links":{"self":[{"href":"https:\/\/labs.wsu.edu\/chenglab\/wp-json\/wp\/v2\/pages\/7"}],"collection":[{"href":"https:\/\/labs.wsu.edu\/chenglab\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/labs.wsu.edu\/chenglab\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/labs.wsu.edu\/chenglab\/wp-json\/wp\/v2\/users\/17550"}],"replies":[{"embeddable":true,"href":"https:\/\/labs.wsu.edu\/chenglab\/wp-json\/wp\/v2\/comments?post=7"}],"version-history":[{"count":20,"href":"https:\/\/labs.wsu.edu\/chenglab\/wp-json\/wp\/v2\/pages\/7\/revisions"}],"predecessor-version":[{"id":253,"href":"https:\/\/labs.wsu.edu\/chenglab\/wp-json\/wp\/v2\/pages\/7\/revisions\/253"}],"wp:attachment":[{"href":"https:\/\/labs.wsu.edu\/chenglab\/wp-json\/wp\/v2\/media?parent=7"}],"wp:term":[{"taxonomy":"wsuwp_university_location","embeddable":true,"href":"https:\/\/labs.wsu.edu\/chenglab\/wp-json\/wp\/v2\/wsuwp_university_location?post=7"},{"taxonomy":"wsuwp_university_org","embeddable":true,"href":"https:\/\/labs.wsu.edu\/chenglab\/wp-json\/wp\/v2\/wsuwp_university_org?post=7"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}