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

破译新型微肽在心脏功能和功能障碍中的作用

基本信息

批准号：
9006942
负责人：
RHONDA BASSEL-DUBY
金额：
$ 55.48万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-16 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9006942
关键词：
Actomyosin Amino Acids Animals Binding Biochemical Biological Biological Assay Ca(2+)-Transporting ATPase Calcineurin Calcium Cardiac Cardiac Myocytes Cell membrane Characteristics Confocal Microscopy Cytosol DNA Sequence Defect Disease Disease model Electron Microscopy Family Functional disorder Goals Growth Heart Heart Diseases Heart failure Homeostasis In Vitro Knockout Mice Mass Spectrum Analysis Measurement Membrane Metabolism Methodology Mus Muscle function Muscle relaxation phase Mutagenesis Names Open Reading Frames Pathology Peptides Physiological Physiology Plant Genome Protein phosphatase Proteins Pump RNA Regulatory Pathway Relaxation Role Sarcomeres Sarcoplasmic Reticulum Second Messenger Systems Signal Pathway Signal Transduction Signal Transduction Pathway Skeletal Muscle Stimulus Stress Striated Muscles Structure Untranslated RNA Yeasts base extracellular frontier heart function in vivo loss of function mutant neglect novel overexpression phospholamban public health relevance response reuptake sarcolipin second messenger yeast two hybrid system

项目摘要

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.

描述（由申请人提供）：Ca2+ 通过充当肌节收缩机制的主要调节器和控制心脏生长、代谢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 Ca2+ 处理受到严格调节。通过肌浆网 (SR) 和质膜中的 Ca2+ 泵维持细胞内 Ca2+ 水平比细胞外和 SR 低约 10,000 倍SR 膜释放的 Ca2+ 会暂时增加细胞质中的 Ca2+ 水平，触发肌节内的肌动球蛋白跨桥形成，从而产生肌浆网 Ca2+-ATP 酶 (SERCA) 将 Ca2+ 重新摄取到 SR 中，这是肌肉松弛所必需的。并恢复随后的收缩-舒张周期的 SR Ca2+ 水平，因此 SERCA 充当心脏功能以及心脏功能的中央调节器。导致心脏病的致病信号级联反应心脏中 SERCA 的活性受到受磷蛋白 (PLN) 的调节，PLN 是一种与 SR 膜中的 SERCA 相互作用并降低 Ca2+ 泵活性的微小肽。注释为长非编码RNA实际上编码了一种以前未被识别的微肽，我们将其命名为DWORF（矮人开放阅读框），其定位于SR。 DWORF 是心肌细胞中下调最显着的蛋白质之一，表明它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确定 DWORF 的功能。并破译控制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情况下增强心肌收缩力的潜在策略。DWORF 的发现也为我们的研究提供了新的进展。对涉及心脏功能控制的信号传导机制的理解，并提出了微肽在控制心脏生理学和病理学中以前未被认识到的作用。