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Calcineurin compartmentation and regulation of pathological cardiac remodeling

钙调神经磷酸酶的划分和病理性心脏重塑的调节

基本信息

批准号：
10361509
负责人：
Michael Seth Kapiloff
金额：
$ 52.26万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10361509
关键词：
Adrenergic Agents Adult Agonist Allosteric Site Angiotensins Attenuated Binding Ca(2+)-Transporting ATPase Calcineurin Calmodulin Cardiac Cardiac Myocytes Cell membrane Cell physiology Cells Clinical Complex Contracts Coronary artery Coupling Data Dependovirus Diagnosis Diffuse Diglycerides Distal Elements Enzymes Exhibits Family Fluorescence Resonance Energy Transfer G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Gene Targeting Genetic Guanosine Triphosphate Phosphohydrolases Heart Heart Hypertrophy Heart failure Hypertrophy Image Immunosuppressive Agents In Vitro Ion Channel Ischemia Knockout Mice Left Ligation Mediating Membrane Membrane Proteins Modeling Monomeric GTP-Binding Proteins Mus Muscle Cells Myocardial Infarction Myocardial Ischemia N-terminal NFAT Pathway Operative Surgical Procedures Pathologic Phosphoric Monoester Hydrolases Phosphoserine Prevention Protein Isoforms Proteins Pump RHO Effector Domain RNA Interference Rattus Regimen Regulation Reperfusion Injury Reperfusion Therapy Reporter Role Sarcomeres Scaffolding Protein Second Messenger Systems Signal Pathway Signal Transduction Source Specificity Stains Stress Structure Syndrome TRIP10 gene Testing Therapeutic Threonine VIVIT peptide Ventricular Vesicle beta-adrenergic receptor calcineurin phosphatase cardiogenesis cdc42 GTP-Binding Protein experimental study functional independence heart function improved inhibitor insight member mortality mutant myocardial injury new therapeutic target novel novel therapeutic intervention novel therapeutics polyproline pressure receptor recruit response rho sensor theories therapeutic target

项目摘要

The Ca2+/calmodulin-dependent phosphatase calcineurin (CaN, PP2B) is a pleiotropic signaling enzyme important for the regulation of cardiac hypertrophy. While CaN inhibition will attenuate pathological cardiac remodeling, therapeutic targeting of CaN is problematic as clinically established CaN inhibitors are immunosuppressant and as CaN targeting can worsen myocardial injury due to ischemia/reperfusion. In theory, however, if CaN signaling pathways mediating pathological cardiac hypertrophy could be targeted in isolation, a new therapeutic paradigm could be established. Two isoforms of CaNA, α and β, are expressed as proteins equally in the heart, and yet genetic targeting of CaNAβ (PPP3cb) is sufficient to blunt pathological hypertrophy in mice. We recently discovered that CaNAβ2 is targeted through its unique N-terminal polyproline (PP) domain to a myocyte compartment organized by the scaffold protein Cdc4-Interacting Protein 4 (CIP4, TRIP10). Imaging using Forster Resonance Energy Transfer (FRET) reporters revealed that CIP4-bound CaNAβ2 is activated by G-protein coupled receptor signaling, including angiotensin II, α- and β-adrenergic receptors, but not by pacing that induces myocyte contraction. Notably, both CIP4 gene targeting and adeno-associated virus-mediated PP- domain anchoring disruption inhibited cardiac remodeling and improved cardiac function in response to pressure overload. Thus, CaNAβ PP-dependent anchoring constitutes a novel mechanism for specification of CaN function, providing an explanation for the specific role of CaNAβ in the cardiac myocyte, as well as for the important question why hypertrophic CaN signaling is not active in normal contracting myocytes. In this project, we will test the novel hypothesis that in the cardiac myocyte PP-domain anchoring and CIP4 compartmentation confer CaNAβ2 action selectively promoting pathological cardiac hypertrophy, thereby comprising a new therapeutic target for the prevention and/or treatment of heart failure. Specific Aim 1: Localization and function of the CIP4 signaling compartment. This Aim will define CIP4 localization in the myocyte, study the relevance of the various CIP4 domains for myocyte hypertrophy, and explore whether CIP4-associated CaNAβ2 acts locally or distally from CIP4 complexes to promote hypertrophy. Specific Aim 2: Regulation of Ca2+ in the CIP4-CaNAβ2 compartment. Functional independence of a Ca2+ signaling compartment requires mechanisms for both local influx of Ca2+ and for insulating the compartment against elevations in Ca2+ associated with other cellular functions. In this Aim, we will define the source of Ca2+ and how this compartment is insulated using live myocyte imaging. Specific Aim 3: PP-anchored CaNAβ and ischemic heart disease. This aim will test whether targeting of PP-anchored CaNAβ can attenuate the development of heart failure without worsening myocyte survival in ischemic heart disease, These Aims will elucidate how PP-domain-mediated anchoring CaNAβ confers activation within a novel Ca2+ compartment, providing both novel insights regarding specificity in phosphatase signal transduction and further evidence supporting a novel therapeutic approach for heart failure.

钙调素依赖性磷酸酶钙调神经磷酸酶（calcineurin, PP2B）是一种多效性信号转导酶