ER stress, also known as unfolded protein response (UPR) is a critical signaling mechanism that has been implicated in neuron degeneration, cancer, diabetics and other diseases. Recent evidence suggests that UPR is also induced in cardiac myocytes following hemodynamic overload and ischemia/reperfusion insults. Activation of UPR can provide cellular protection against cytoxicity from protein aggregate as in the cases of amyloidosis, or oxidative and ischemic injury. However, prolonged stimulation of UPR can also trigger apoptosis. Therefore, calibrated regulation of UPR may have significant implication in cardiac protection and injury. IRE1 (a or b isoform) is an ER membrane targeted ser/thr protein kinase with specific RNase activity that is critical to UPR as well as ER stress induced JNK activation and cell death, and is essential for normal embryonic development. IRE1 activity is induced during UPR via dimerization and ser/thr trans-phosphorylation. However, the molecular mechanism involved in its dephosphorylation is unknown. Through genome mining, we found a novel Ser/Thr protein phosphatase (PP2Ce) that is highly enriched in brain and heart, and is exclusively targeted on ER membrane and possesses a remarkable selectivity to dephosphorylate IRE1 in vitro and in vivo. Preliminary studies demonstrate that PP2Ce inhibits IRE1 phosphorylation and negatively modulate IRE1 mediated ER stress signaling. This exciting finding leads to our current hypothesis that this novel PP2C isoform is the endogenous IRE1 specific protein phosphatase and has an important role in regulating UPR in heart under pathological conditions. To rigorously test this hypothesis, we propose to accomplish the following three specific aims:
Aim 1. we will determine the role of PP2Ce in regulating UPR in cardiomyocytes in culture.
Aim 2, we will explore the molecular mechanisms of PP2Ce mediated regulation of IRE1 activity.
Aim 3, we will determine the functional significance of PP2Ce mediated regulation in embryonic development in zebrafish.
Aim4, we will use cardiac specific and inducible PP2Ce over-expressor and PP2Ce knockout mouse models to determine the impact of PP2Ce activity on cardiac function and ischemia reperfusion injury in intact animals. From these studies, we will establish the functional role and molecular mechanisms of a novel ER stress signaling component heart and shed new insights to the underlying mechanisms of heart failure. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL070079-06
Application #
7322869
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Przywara, Dennis
Project Start
2002-04-01
Project End
2012-06-30
Budget Start
2007-09-01
Budget End
2008-06-30
Support Year
6
Fiscal Year
2007
Total Cost
$376,385
Indirect Cost
Name
University of California Los Angeles
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Steiger, DeAnna; Yokota, Tomohiro; Li, Jin et al. (2018) The serine/threonine-protein kinase/endoribonuclease IRE1? protects the heart against pressure overload-induced heart failure. J Biol Chem 293:9652-9661
Akaike, Toru; Du, Na; Lu, Gang et al. (2017) A Sarcoplasmic Reticulum Localized Protein Phosphatase Regulates Phospholamban Phosphorylation and Promotes Ischemia Reperfusion Injury in the Heart. JACC Basic Transl Sci 2:160-180
Touma, Marlin; Kang, Xuedong; Gao, Fuying et al. (2017) Wnt11 regulates cardiac chamber development and disease during perinatal maturation. JCI Insight 2:
Rose, Beth A; Yokota, Tomohiro; Chintalgattu, Vishnu et al. (2017) Cardiac myocyte p38? kinase regulates angiogenesis via myocyte-endothelial cell cross-talk during stress-induced remodeling in the heart. J Biol Chem 292:12787-12800
Touma, Marlin; Kang, Xuedong; Zhao, Yan et al. (2016) Decoding the Long Noncoding RNA During Cardiac Maturation: A Roadmap for Functional Discovery. Circ Cardiovasc Genet 9:395-407
Wang, Zhihua; Zhang, Xiao-Jing; Ji, Yan-Xiao et al. (2016) The long noncoding RNA Chaer defines an epigenetic checkpoint in cardiac hypertrophy. Nat Med 22:1131-1139
Gao, Chen; Ren, Shuxun; Lee, Jae-Hyung et al. (2016) RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart failure. J Clin Invest 126:195-206
Yokota, Tomohiro; Wang, Yibin (2016) p38 MAP kinases in the heart. Gene 575:369-376
Feng, Jiaying; Gong, Danyang; Fu, Xudong et al. (2015) M1 of Murine Gamma-Herpesvirus 68 Induces Endoplasmic Reticulum Chaperone Production. Sci Rep 5:17228
Sun, Haipeng; Wang, Yibin (2014) Interferon regulatory factors in heart: stress response beyond inflammation. Hypertension 63:663-4

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