The Role of Perinuclear Calcium for The induction of Cardiac Hypertrophy

 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，左心室肥大是扩张型心肌病和心力衰竭发展的主要危险因素。钙调蛋白依赖性蛋白磷酸酶钙调磷酸酶（CaN）是调节病理性重塑的关键信号蛋白，并且已提出操纵CaN活性作为治疗策略。然而，经典的CaN抑制剂是免疫抑制剂，并且具有不良副作用，使得这种药物选择对于心脏病的长期治疗不可行。我们建议通过破坏CaN定位靶向CaN的特定微结构域将开辟用于治疗肥大的药物设计的新途径。特别是，我们已经表明，支架蛋白mAKAPβ结合CaN及其下游底物MEF2D，从而产生CaN信号传导的微域。此外，mAKAPβ表达在体内是诱导响应于压力超负荷的病理性重塑所必需的。我们的中心假设是，特定的CaN池局限于选择的细胞内区室，如由mAKAPβ组织的区室，为局部激活和底物定义提供了分子基础。我们的三个具体目标将测试mAKAPβ结合的CaN是否受核周Ca2+隔室（Aim 1）的调节，该隔室控制MEF2D基因转录（Aim 2），并且可以选择性地靶向心力衰竭的药物治疗（Aim 3）。

 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).