Modulating calcineurin Signaling pathways in Muscle

超出所提供的空间。3alcineurin是一种钙调节的丝氨酸/苏氨酸蛋白磷酸酶。钙调神经磷酸酶信号转导通路参与多种细胞类型的发育和稳态调节。我们最近描述了一个新的蛋白质家族，在心脏和骨骼肌中富集，称为调节性钙调神经磷酸酶相互作用蛋白（MCIP）。这些蛋白质可以与钙调磷酸酶的活性位点形成物理复合物并抑制磷酸酶活性。反过来，哺乳动物MCIP 1基因的转录被钙调磷酸酶激活。我们的目标是由MCIP家族的蛋白质作为钙调磷酸酶活性的内源性调节剂的主要假设驱动。在最初的研究中，我们已经表明，在心肌细胞中表达人类MCIP 1的转基因小鼠对各种肥大刺激具有抵抗力。未来发展的措施，以增加表达或活性的MCIP蛋白选择性在心脏内可能有临床价值的预防心力衰竭。该补助金的目标是：1）确定MCIP与钙调神经磷酸酶的相互作用，2）检测MCIP基因表达和MCIP蛋白水平在心肌和骨骼肌重塑过程中的变化，以完善我们整合MCIP转录的模型，MCIP蛋白稳定性和钙调磷酸酶活性3）研究MCIP的心脏保护潜力，并测试我们的模型，MCIP是钙调神经磷酸酶信号的内源性调节剂。这些研究将阐明MCIP蛋白的机制、调节和生理作用，并为调节钙调神经磷酸酶的新治疗方法奠定基础。性能现场=

EXCEED THE SPACE PROVIDED. 3alcineurin is a calcium regulated serine/threonine protein phosphatase. The calcineurin signal transduction pathway is involved in developmental and homeostatic regulation of a wide variety of cell types. We have recently described a new family of proteins that are enriched in heart and skeletal muscle called Modulatory Calcineurin-lnteracting Proteins (MCIPs). These proteins can form a physical complex with the active site of calcineurin and inhibit phosphatase activity. In turn, transcription of the mammalian MCIP1 gene is activated by calcineurin. Our goals are driven by the primary hypothesis that the MCIP family of proteins function as endogenous modulators of calcineurin activity. In initial studies we have shown that transgenic mice with elevated expression of human MCIP1 in cardiomyocytes are resistant to a variety of hypertrophic stimuli. Future development of measures to increase expression or activity of MCIP proteins selectively within the heart may have clinical value for prevention of heart failure. The goals of this grant are: 1) To define the interaction of MCIP with calcineurin, 2) To examine changes in the expression of MCIP genes and in the level of MCIPprotein during cardiac and skeletal muscle remodeling in order to refine our model integrating MCIP transcription, MCIP protein stability and calcineurin activity 3) To examine the cardioprotective potential of MCIPs and test our model that MCIPs are endogenous regulators of calcineurin signaling. These studies will clarify the mechanism, regulation and physiological role of MCIP proteins and create the basis for novel therapeutic approaches to regulating calcineurin. PERFORMANCE SITE ========================================Section End===========================================