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：
8597835
负责人：
CYNTHIA A CARNES
金额：
$ 36.53万
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/8597835
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）：我们建议定义腺苷受体（ARS）在中等节点（SAN）Pacemaker复合物中的表达和功能心。该研究的总体目的是了解腺苷和ARS在心力衰竭（HF）期间SAN功能障碍和心律不齐的作用。我们的中心假设是，HF依赖腺苷的重塑和信号导致HF中的SAN功能障碍。我们将使用一种综合方法来研究犬和人心中的正常生理和HF诱导的重塑过程，以描绘腺苷在SAN的正常和病理功能中的作用。互补的犬科研究旨在为人类SAN的有针对性，有效研究提供框架。我们具有专业知识，实验模型和人体组织的访问，以评估我们的假设，即AR信号对于正常的SAN功能以及HF诱导的SAN心律不齐至关重要。初步研究支持目标，实验方法的可行性以及犬模型作为人类SAN的替代物的有效性 - 现在是新的试点研究直接证明的。我们已经准备好进行该项目，因为Fedorov博士（P.I.）具有独特的光学映射专业知识来评估人类的SAN结构和功能；与卡恩斯博士（Co-P.I。）的专业知识相结合，具有与临床相关的心力衰竭隔离肌细胞生理学（ION Currents）的模型，将允许解决此问题的综合方法。确定导致异常SAN功能的空间，结构和信号传导元素将描绘易感成分，从而导致潜在的致命性心律不齐。这将允许开发用于SAN功能和功能障碍的新颖的“蓝图”，为开发源自San Pacemaker综合体的人体心律不齐的高度靶向和有效治疗的基础。