Anchored Phosphatase and Transcription Factor Regulation in the Heart

锚定磷酸酶和转录因子在心脏中的调节

基本信息

批准号：
9412882
负责人：
Kimberly L Dodge-Kafka
金额：
$ 45.92万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9412882
关键词：
Adverse effects Affect Amyloid beta-Protein Apoptosis Attenuated Binding Biosensor Calcineurin Calcineurin inhibitor Calmodulin Cardiac Cardiac Myocytes Catecholamines Cessation of life Chronic Disease Chronic stress Cyclosporine DNA Binding Data Dependovirus Development Diagnosis Dilated Cardiomyopathy Disease Drug Design Enzymes Fibrosis Gene Expression Gene Targeting Genetic Genetic Transcription Growth Heart Heart Diseases Heart Hypertrophy Heart failure Human Hypertrophy Immunosuppression Immunosuppressive Agents In Vitro Infusion procedures Ions Left Ventricular Hypertrophy Link Measures Mediating Metabolism Molecular Mus Muscle Muscle Cells Muscle Proteins Neurons Nuclear Nuclear Envelope Operative Surgical Procedures PPP3CB gene Pathologic Peptides Pharmaceutical Preparations Pharmacology Phosphoric Monoester Hydrolases Phosphorylation Physiological Post-Translational Protein Processing Prevention Protein Dephosphorylation Protein Isoforms Protein phosphatase Publishing Regimen Regulation Reporting Risk Factors Scaffolding Protein Signal Transduction Signaling Protein Specific qualifier value Syndrome Testing Therapeutic Time Transcription Coactivator base calcineurin phosphatase cardiogenesis in vivo interstitial mortality novel therapeutic intervention pleiotropism pressure prevent promoter protein B public health relevance recruit response scaffold targeted treatment therapy design transcription factor

项目摘要

DESCRIPTION (provided by applicant): Cardiac hypertrophy is the primary compensatory response of the heart to chronic stress. Accordingly, left ventricular hypertrophy is a major risk factor for the development of dilated cardiomyopathy and heart failure. The Ca2+/calmodulin-dependent protein phosphatase Calcineurin (CaN) is a key signaling protein regulating pathological remodeling, and manipulation of CaN activity has been proposed as a therapeutic strategy. However, classical inhibitors of CaN are immunosuppressants and have adverse side effects, making this drug option unfeasible for long-term treatment of cardiac disease. We propose that targeting specific microdomains of CaN via disrupting CaN localization will open up new avenues of drug design for the treatment of hypertrophy. In particular, we have shown that the scaffolding protein mAKAPβ binds both CaN and its downstream substrate MEF2D, hence creating a microdomain of CaN signaling. Additionally, mAKAPβ expression is required in vivo for the induction of pathological remodeling in response to pressure overload. Our central hypothesis states that specific pools of CaN confined to select intracellular compartments such as that organized by mAKAPβ provides the molecular basis for both localized activation and definition of substrate. Our three specific aims will test whether mAKAPβ-bound CaN is regulated by a perinuclear Ca2+ compartment (Aim 1) that controls MEF2D gene transcription (Aim 2) and that may be selectively targeted for drug therapy for heart failure (Aim 3).

描述（由申请人提供）：心脏肥大是心脏对慢性应激的主要代偿反应，因此，左心室肥大是发生扩张型心肌病和心力衰竭的主要危险因素。 (CaN) 是调节病理重塑的关键信号蛋白，控制 CaN 活性已被提议作为一种治疗策略。 CaN 是免疫抑制剂，具有不良副作用，因此该药物不适合长期治疗心脏病。我们认为，通过破坏 CaN 定位来靶向 CaN 的特定微结构域将为治疗肥大开辟新的药物设计途径。特别是，我们已经证明支架蛋白 mAKAPβ 结合 CaN 及其下游底物 MEF2D，因此创建了 CaN 信号传导的微结构域。此外，mAKAPβ 表达也是必需的。我们的中心假设指出，特定的 CaN 池局限于特定的细胞内区室，例如由 mAKAPβ 组织的区室，为我们的三种特定底物提供了分子基础。目标将测试 mAKAPβ 结合的 CaN 是否受到控制 MEF2D 基因转录（目标 2）的核周 Ca2+ 区室（目标 1）的调节，并且可以选择性地用于心脏药物治疗失败（目标 3）。