Deciphering the role of a novel micropeptide in cardiac function and dysfunction

 描述(由申请人提供)：钙离子通过作为肌节收缩机械的主要调节器和控制心脏生长、新陈代谢和病理重塑的信号转导途径中的第二信使来控制心脏功能。肌浆网(SR)和质膜上的钙泵严格调节横纹肌中的钙离子转运，使细胞内的钙离子水平比细胞外和肌浆网的浓度低约10,000倍。肌浆网膜上的Ca~(2+)释放瞬间增加胞浆中的Ca~(2+)水平，触发肌球蛋白在肌节内跨桥形成，产生收缩力量。肌浆网Ca~(2+)-ATPase(SERCA)重新摄取Ca~(2+)进入SR是肌肉松弛所必需的，并为随后的收缩-松弛循环恢复SR的Ca~(2+)水平。因此，SERCA作为心脏功能的中央调节器，以及驱动心脏病的致病信号级联反应。心脏中SERCA的活性受磷蛋白(PLN)的调节，PLN是一种与SR膜上的SERCA相互作用并降低钙泵活性的小肽。最近，我们发现心脏特异的RNA被注释为一个长的非编码RNA，实际上编码了一个以前不被识别的微肽，我们将其命名为DWORF(Dwarf Open Reader Frame)。DWORF定位于心肌细胞的SR，并与SERCA相互作用。DWORF是衰竭心脏中表达下调最严重的蛋白质之一，表明它可能参与心脏对应激和收缩功能障碍的反应。这个项目的总体目标是定义DWORF的功能，并破译控制其在正常和疾病心脏中表达的机制。操纵这种新型微肽的活性代表了一种在心脏病背景下增强心脏收缩能力的潜在策略。DWORF的发现也为我们理解参与控制心脏功能的信号机制提供了新的途径，并暗示了微肽在心脏生理和病理控制中的先前未知的作用。

 DESCRIPTION (provided by applicant): Ca2+ controls cardiac function by acting as the primary regulator of the sarcomeric contractile machinery and as a second messenger in the signal transduction pathways that control cardiac growth, metabolism and pathological remodeling. Ca2+ handling in striated muscle is tightly regulated by Ca2+ pumps in the sarcoplasmic reticulum (SR) and plasma membranes that maintain intracellular Ca2+ levels ~10,000-fold lower than extracellular and SR concentrations. Ca2+ release from the SR membrane transiently increases Ca2+ levels in the cytosol, triggering actomyosin cross-bridge formation within the sarcomere to generate contractile force. Reuptake of Ca2+ into the SR by sarcoplasmic reticulum Ca2+-ATPase (SERCA) is necessary for muscle relaxation and restores SR Ca2+ levels for subsequent contraction-relaxation cycles. SERCA thus serves as a central regulator of cardiac function, as well as the pathogenic signaling cascades that drive heart disease. The activity of SERCA in the heart is modulated by phospholamban (PLN), a tiny peptide that interacts with SERCA in the SR membrane and diminishes Ca2+ pump activity. Recently, we discovered that a cardiac- specific RNA annotated as a long noncoding RNA actually encodes a previously unrecognized micropeptide, which we named DWORF (Dwarf Open Reading Frame). DWORF is localized to the SR of cardiomyocytes and interacts with SERCA. DWORF is among the most dramatically down-regulated proteins in failing hearts, pointing to its potential involvement in the response of the heart to stress and contractile dysfunction. The overall goals of this project are to define the functions of DWORF and to decipher the mechanisms that govern its expression in normal and diseased hearts. Manipulation of the activity of this novel micropeptide represents a potential strategy to enhance cardiac contractility in the setting of heart disease. The discovery of DWORF also provides a new inroad into our understanding of the signaling mechanisms involved in the control of cardiac function and suggests a previously unrecognized role for micropeptides in the control of cardiac physiology and pathology.