Modulating calcineurin signaling pathways in muscle

描述（由申请人提供）：钙调磷酸酶是一种钙调节的丝氨酸/苏氨酸蛋白磷酸酶。钙调磷酸酶信号转导途径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富含心脏和骨骼肌的新蛋白家族，称为调节性钙调磷酸酶相互作用蛋白（MCIPs）。这些蛋白可与钙调磷酸酶活性位点形成物理复合物，抑制磷酸酶活性。反过来，哺乳动物MCIP1基因的转录被钙调磷酸酶激活。我们的目标是由MCIP家族蛋白作为钙调磷酸酶活性的内源性调节剂的主要假设驱动的。在最初的研究中，我们已经表明，心肌细胞中人类MCIP1表达升高的转基因小鼠对各种肥厚性刺激具有抗性。未来发展选择性地增加心脏内MCIP蛋白表达或活性的措施可能对预防心力衰竭具有临床价值。本基金的目标是：1)确定MCIP与钙调磷酸酶的相互作用；2)检测心脏和骨骼肌重塑过程中MCIP基因表达和MCIP蛋白水平的变化，以完善整合MCIP转录、MCIP蛋白稳定性和钙调磷酸酶活性的模型；3)检测MCIP的心脏保护潜力，并验证MCIP是钙调磷酸酶信号的内源性调节因子的模型。这些研究将阐明MCIP蛋白的机制、调控和生理作用，并为调节钙调磷酸酶的新治疗方法奠定基础。

DESCRIPTION (provided by applicant): Calcineurin 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 MCIP protein 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.