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（由适用提供）：心脏肥大是心脏对慢性应激的主要补偿反应。根据上述，左心室肥大是发展膨胀心肌病和心力衰竭的主要危险因素。 Ca2+/钙调蛋白依赖性蛋白光培养酶钙调蛋白（CAN）是一种关键的信号蛋白调节重塑，并且已经提出了对CAN活性的操纵作为治疗策略。但是，罐头的经典抑制剂是免疫抑制剂，并且具有不良的副作用，这使得这种药物的长期治疗不可行。我们建议，通过破坏CAN定位来靶向罐头的特定微区域将为治疗肥大的新途径打开新的药物设计途径。特别是，我们已经表明，脚手架蛋白makapβ都结合了CAN及其下游底物MEF2D，因此产生了CAN信号传导的微域。另外，在体内需要MAKAPβ表达，以响应压力超负荷而诱导病理重塑。我们的中央假设指出，特定的特定池可以局限于选择细胞内室，例如由makapβ组织的池，为底物的局部激活和定义提供了分子基础。我们的三个特定目标将测试是否可以通过控制MEF2D基因转录（AIM 2）的核周Ca2+室（AIM 1）来调节MAKAPβ结合的能力（AIM 1），并且可以选择性地针对用于心力衰竭的药物治疗（AIM 3）。