Integration of structure and signaling in cardiac pacemaker function

心脏起搏器功能中结构和信号的整合

基本信息

批准号：
8704998
负责人：
CYNTHIA A CARNES
金额：
$ 37.7万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8704998
关键词：
3-Dimensional Action Potentials Adenosine Adenosine A1 Receptor Arrhythmia Artificial cardiac pacemaker Biochemistry Biological Models Canis familiaris Cardiac Cells Cessation of life Chronic Clinical Research Complex Coupled Data Development Elements Experimental Models Foundations Functional disorder GIRK1 subunit, G protein-coupled inwardly-rectifying potassium channel GIRK4 subunit, G protein-coupled inwardly-rectifying potassium channel GTP-Binding Proteins Goals Heart Heart Arrest Heart Rate Heart failure Heterogeneity Human Ions Lead Link Maps Mental Depression Metabolic stress Metabolism Modeling Molecular Morbidity - disease rate Muscle Cells Myocardium Optics Pacemakers Pathologic Pathway interactions Patients Physiological Physiology Pilot Projects Process Property Purinergic P1 Receptors Receptor Signaling Regulation Research Research Design Resolution Role Signal Pathway Signal Transduction Sinoatrial Node Spatial Distribution Structure Testing Time United States base clinically relevant effective therapy electronic pacemaker human tissue improved innovation meetings mortality novel optical imaging public health relevance translational study

项目摘要

DESCRIPTION (provided by applicant): We propose to define the expression and function of the adenosine receptors (ARs) in the sino-atrial node (SAN) pacemaker complex in order to elucidate the role of adenosine signaling in heart rate regulation in failing and non-failing human hearts. The overall objective of the study is to understand the role of adenosine and ARs in SAN dysfunction and arrhythmias during heart failure (HF). Our central hypothesis is that SAN dysfunction in HF results from adenosine-dependent remodeling and signaling. We will use an integrated approach to study normal physiologic and HF-induced remodeling processes in canine and human hearts to delineate the role of adenosine in the normal and pathologic function of the SAN. The complementary canine studies are designed to provide a framework for the targeted, efficient study of the human SAN. We have the expertise, experimental model, and human tissue access to evaluate our hypothesis that AR signaling is critical for both normal SAN function, as well as HF-induced SAN arrhythmias. Preliminary studies support the aims, feasibility of the experimental approaches, and the validity of the canine model as a surrogate for human SAN - now directly demonstrated by new pilot studies. We are well prepared to undertake this project because the Dr. Fedorov (P.I.) has unique optical mapping expertise to evaluate human SAN structure and function; this, combined with the expertise of Dr. Carnes (Co-P.I.) with a clinically relevant model of heart failure isolated myocyte physiology (ion currents) will permit an integrated approach to this problem. Identifying the spatial, structural and signaling elements contributing to abnormal SAN function will delineate the susceptible components causing potentially lethal arrhythmias. This will permit development of a novel 'blueprint' for SAN function and dysfunction, providing a foundation for the development of highly targeted and effective treatments for human arrhythmias originating in the SAN pacemaker complex.

描述（由申请人提供）：我们建议定义窦房结（SAN）起搏器复合体中腺苷受体（AR）的表达和功能，以阐明腺苷信号传导在心衰和非心律失常患者心率调节中的作用。 -失败的人类心。该研究的总体目标是了解腺苷和 AR 在心力衰竭 (HF) 期间 SAN 功能障碍和心律失常中的作用。我们的中心假设是心力衰竭中的 SAN 功能障碍是由腺苷依赖性重塑和信号转导引起的。我们将使用综合方法来研究犬和人类心脏的正常生理和高频诱导的重塑过程，以描述腺苷在 SAN 正常和病理功能中的作用。互补的犬类研究旨在为人类 SAN 的有针对性的、有效的研究提供一个框架。我们拥有专业知识、实验模型和人体组织来评估我们的假设，即 AR 信号传导对于正常 SAN 功能以及 HF 诱导的 SAN 心律失常至关重要。初步研究支持了实验方法的目标、可行性以及犬类模型作为人类 SAN 替代品的有效性——现在已由新的试点研究直接证明。我们已经做好了承接这个项目的充分准备，因为 Fedorov 博士（P.I.）拥有独特的光学测绘专业知识来评估人体 SAN 结构和功能；结合 Carnes 博士（Co-P.I.）的专业知识以及临床相关的心力衰竭分离心肌细胞生理学模型（离子流）的专业知识，将允许采用综合方法解决该问题。识别导致 SAN 功能异常的空间、结构和信号元件将描述导致潜在致命性心律失常的易感成分。这将为 SAN 功能和功能障碍开发新的“蓝图”，为开发针对源自 SAN 起搏器复合体的人类心律失常的高度针对性和有效的治疗方法奠定基础。