Signaling in Inherited and Acquired Sodium Channel Gain of Function

遗传性和获得性钠通道功能增益中的信号传导

• 批准号: 10201723
• 负责人: Steven Poelzing
• 金额: $ 66.7万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201723
• 关键词: Action Potentials; Address; Adhesions; Age; Agonist; Anatomy; Animal Model; Animals; Arrhythmia; Attenuated; Carbenoxolone; Cardiac; Cavia; Cell Size; Cell model; Cells; Characteristics; Computer Models; Computer Simulation; Connexin 43; Coronary Arteriosclerosis; Coupling; Diabetes Mellitus; Disease; Disease Progression; Early Diagnosis; Electrocardiogram; Etiology; Event; Exhibits; Failure; Feedback; Female; Gap Junctions; Gender; Genes; Genetic; Genetic study; Heart Rate; Heart failure; Incidence; Individual; Inherited; Intercalated disc; Intervention; Investigation; Life; Long QT Syndrome; Mediating; Membrane; Membrane Potentials; Modeling; Modification; Muscle Cells; Mutation; Optics; Organism; Osmolite; Pathologic; Patients; Peptides; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Protein Isoforms; Puberty; Reproducibility; Risk; Role; Severities; Signal Transduction; Sodium; Sodium Channel; Structure; Sudden Death; Symptoms; Syndrome; Testing; Therapeutic Agents; Tissue Model; Tissues; Translating; Treatment Efficacy; Ventricular; age related; aged; attenuation; base; design; detection test; driving force; efficacy testing; electric field; experimental study; extracellular; gain of function; gain of function mutation; indium arsenide; loss of function; male; mouse model; novel; prevent; ranolazine; response; simulation; sudden cardiac death; tissue preparation; voltage

PROJECT SUMMARY Gain-of-function mutations in the genes encoding or age related modifications of the cardiac isoform of the voltage-gated sodium channel have been associated with the Long-QT Syndrome Type 3 (LQT3) and heart failure. The genetic form of sodium channel gain of function disease LQT3 represents an exemplar for elucidating the role sodium channels play in sudden death independent of systemic remodeling. The principal issue that will be addressed in this application is the role intercellular coupling plays in translating a cellular pathologic response into a tissue level response that causes sudden cardiac death. In short, if cells electrically communicate only by gap junctional coupling, then statistically the chance of sudden death should be low and only occur after substantial gap junction loss of function. However, if cells can also communicate via electric fields generated in very narrow spaces between cells (ephaptic coupling), then pathologic activity should manifest during substantial ephaptic remodeling. Additionally, symptoms of LQT3 do not manifest until sometime during or after puberty, suggesting that young organisms are protected against life-threatening cardiac events by some type of age related remodeling. Since gap junctions redistribute around cells, but do not necessarily decrease expression, the gap junction coupling hypothesis remains speculative at best. However, since the determinants of cellular excitability and ephaptic coupling change with age, the hypothesis that ephaptic coupling modulates sudden death during gain-of-sodium function requires investigation. Upon successful completion of these aims, we will produce new theoretical underpinnings of LQT3 and heart failure that will help design new early detection tests and suggest new treatments during disease progression.

项目摘要 基因编码的功能获得性突变或心脏同种型的年龄相关修饰， 电压门控钠通道与3型长QT综合征（LQT3）和心脏病有关。 失败钠通道获得性功能疾病LQT3的遗传形式为阐明 钠离子通道在猝死中的作用与系统重构无关。 在本申请中要解决的主要问题是细胞间偶联在翻译中的作用。 从细胞病理反应转变为组织水平的反应导致心脏性猝死。简言之，如果细胞 电通信仅通过间隙连接耦合，那么统计上猝死的机会应该 低，仅发生在实质性间隙连接功能丧失之后。然而，如果细胞也可以通过 在细胞之间非常狭窄的空间中产生的电场（肝细胞耦合），那么病理活动应该 表现在肝实质重塑时 此外，LQT3的症状直到青春期或青春期后的某个时候才表现出来，这表明年轻人 生物体通过某些类型的年龄相关的重塑而免受危及生命的心脏事件的影响。以来 缝隙连接重新分布在细胞周围，但不一定减少表达，差距连接偶联 假设充其量只是推测。然而，由于细胞兴奋性和肝纤维化的决定因素 偶联随年龄变化，在钠增加过程中，肝细胞偶联调节猝死的假设 功能需要调查。 在成功完成这些目标后，我们将产生LQT3和心脏的新理论基础， 这将有助于设计新的早期检测测试，并在疾病进展期间提出新的治疗方法。

项目成果

Dual regulation by subcellular calcium heterogeneity and heart rate variability on cardiac electromechanical dynamics.

• DOI: 10.1063/5.0019313
• 发表时间: 2020-09
• 期刊: Chaos
• 影响因子: 2.9
• 作者: Vrishti M. Phadumdeo;S. Weinberg

Role of ephaptic coupling in discordant alternans domain sizes and action potential propagation in the heart.

• DOI: 10.1103/physreve.107.054407
• 发表时间: 2023-05
• 期刊: PHYSICAL REVIEW E
• 影响因子: 2.4
• 作者: Otani, Niels F.;Figueroa, Eileen;Garrison, James;Hewson, Michelle;Munoz, Laura;Fenton, Flavio H.;Karma, Alain;Weinberg, Seth H.
• 通讯作者: Weinberg, Seth H.

Ephaptic Coupling as a Resolution to the Paradox of Action Potential Wave Speed and Discordant Alternans Spatial Scales in the Heart.

• DOI: 10.1103/physrevlett.130.218401
• 发表时间: 2023-05-26
• 期刊: PHYSICAL REVIEW LETTERS
• 影响因子: 8.6
• 作者: Otani, Niels F.;Figueroa, Eileen;Garrison, James;Hewson, Michelle;Munoz, Laura;Fenton, Flavio H.;Karma, Alain;Weinberg, Seth H.
• 通讯作者: Weinberg, Seth H.