Mechanisms of Gap Junction Regulation

间隙连接调节机制

• 批准号: 10297944
• 负责人: PAUL L SORGEN
• 金额: $ 49.63万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10297944
• 关键词: Acute; Affect; Arrhythmia; Basic Science; Binding; Cardiac; Cells; Characteristics; Chronic; Clinical; Connexin 43; Connexins; Coupling; Data; Development; Disease; Distal; F-Actin; Gap Junctions; Growth; Growth Factor; Heart; Heart Diseases; Heart failure; Hypertrophy; In Vitro; Infarction; Integral Membrane Protein; Intercalated disc; Intercellular Communication Inhibition; Ion Exchange; Ischemia; Knowledge; Lateral; Lead; Left ventricular structure; Link; Mediating; Membrane; Morphology; Muscle Cells; Myocardial Infarction; Myocardial dysfunction; Myocardium; Pathologic; Pathology; Pathway interactions; Permeability; Phosphorylation; Phosphotransferases; Process; Property; Proteins; Regulation; Research; Role; SRC gene; Signal Transduction; Signaling Molecule; Testing; Therapeutic; Therapeutic Intervention; Tubulin; Up-Regulation; Ventricular; Ventricular Arrhythmia; base; beta Tubulin; cytokine; density; drebrins; effective therapy; experimental study; gap junction channel; heart rhythm; human disease; insight; intercellular communication; interdisciplinary approach; interest; intermolecular interaction; molecular mass; mouse model; novel; prevent; voltage

Abstract: Gap junctions are integral membrane proteins that enable the direct cytoplasmic exchange of ions and low molecular-mass metabolites between adjacent cells. They provide a pathway for propagating and/or amplifying the signal transduction cascades triggered by cytokines, growth factors, and other cell signaling molecules involved in growth regulation and development. Dysfunctional intercellular communication via gap junctions has been implicated in causing many human diseases. The objective of this project is to use a multi-disciplinary approach to identify the key intrinsic regulatory mechanisms that are responsible for Cx43 and Cx45 function. The central hypothesis is that unique intermolecular interactions within the divergent CT domain of connexins affect gap junction regulation. More specifically, we hypothesize that after myocardial infarction, differential regulation of Cx43 and Cx45 involves specific phosphorylations and protein interactions of their CT domain. The significance of this proposal is that discovery of how interactions mediated by the CT domain can be modulated would open the door to strategies to ameliorate pathological effects of altered connexin regulation in the failing heart. The following Specific Aims are proposed to investigate this concept: 1) What drives Cx43 away from gap junctions/intercalated discs in vitro and in a murine model of myocardial infarction? and 2) What promotes Cx45 gap junction/intercalated disc localization and is Cx45 expression in left ventricle hypertrophy after myocardial infarction an arrhythmogenic substrate? Upon completion of this project, we expect to describe novel mechanisms by which phosphorylation and protein partners regulate Cx43 and Cx45 function and strategies by which the pathological effects of Pyk2, Src, and Cx45 upregulation in failing hearts may be lessened.

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