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

 描述（由申请人提供）：Ca 2+通过作为肌节收缩机制的主要调节剂和控制心脏生长、代谢和病理性重塑的信号转导途径中的第二信使来控制心脏功能。横纹肌中的Ca 2+处理受到肌浆网（SR）和质膜中的Ca 2+泵的严格调节，其维持细胞内Ca 2+水平比细胞外和SR浓度低约10，000倍。从SR膜释放的Ca 2+瞬时增加胞质溶胶中的Ca 2+水平，触发肌节内的肌动球蛋白跨桥形成以产生收缩力。肌浆网Ca ~（2+）-ATP酶（SERCA）将Ca ~（2+）重摄取到SR中是肌肉松弛所必需的，并且恢复SR Ca ~（2+）水平以用于随后的收缩-松弛周期。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。SERCA在心脏中的活性由受磷蛋白（PLN）调节，受磷蛋白是一种与SR膜中的SERCA相互作用并降低Ca 2+泵活性的微小肽。最近，我们发现一种被注释为长非编码RNA的心脏特异性RNA实际上编码一种以前未被识别的微肽，我们将其命名为DWORF（Dwarf Open阅读Frame）。DWORF定位于心肌细胞的SR并与SERCA相互作用。DWORF是衰竭心脏中最显著下调的蛋白质之一，表明其可能参与心脏对压力和收缩功能障碍的反应。该项目的总体目标是定义DWORF的功能，并破译其在正常和患病心脏中表达的机制。操纵这种新型微肽的活性代表了在心脏病的情况下增强心脏收缩力的潜在策略。DWORF的发现也为我们理解参与心脏功能控制的信号传导机制提供了新的进展，并表明了以前未被认识到的微肽在心脏生理和病理控制中的作用。

 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.