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（通过应用程序证明）：CA2+通过充当肌膜收缩机械的主要调节器，并在信号传输中ca2+ pumpers（sarcoplum pumps）（ SR）和质膜维持细胞内Ca2+水平ND SR浓度。Ca2+从膜中释放。松弛周期以及心脏病的致病信号级联是模块化禁令（PLN）的潮汐，与膜中的SERCA相互作用并减少了CA2+泵的活性。 RNA作为EAD框架的注释。在正常和患病的心脏中的表达的机制。在控制心脏和Suggs中，微肽在心脏生理和病理中的控制作用。