Anchored Phosphatase and Transcription Factor Regulation in the Heart

 描述(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，左心室肥厚是发生扩张型心肌病和心力衰竭的主要危险因素。钙调素依赖的蛋白磷酸酶钙调神经磷酸酶(CaN)是调节病理重塑的关键信号蛋白，调控CaN活性被认为是一种治疗策略。然而，经典的CaN抑制剂是免疫抑制剂，具有不良副作用，使该药物选择不适用于心脏病的长期治疗。我们认为，通过干扰CaN的定位来靶向CaN的特定微域将为治疗肥厚的药物设计开辟新的途径。特别是，我们已经证明了支架蛋白mAKAPβ与CaN及其下游底物MEF2D结合，从而创建了CaN信号的微域。此外，在体内，mAKAPβ的表达是诱导压力超负荷所致的病理重塑所必需的。我们的中心假设是，特定的CaN池被限制在选择的细胞内隔室，例如由mAKAPβ组织的那些，为局部激活和底物的定义提供了分子基础。我们的三个特定目标将测试mAKAPβ结合的CaN是否受控制MEF2D基因转录的核周钙室(Aim 1)调节(Aim 2)，并可能选择性地作为心力衰竭药物治疗的靶点(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).