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Signaling in Inherited and Acquired Sodium Channel Gain of Function

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
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-07-01 至 2023-06-30

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中文摘要
翻译
项目总结 心脏亚型的编码基因或年龄相关修饰的功能获得突变 电压门控钠通道与长QT综合征3型(LQT3)和心脏 失败了。功能性疾病LQT3的钠通道获得的遗传形式代表了阐明的范例 钠通道在不依赖全身重构的猝死中所起的作用。 在此应用程序中要解决的主要问题是细胞间耦合在翻译过程中所起的作用 引起心脏猝死的组织水平反应的一种细胞病理反应。简而言之,如果单元格 仅通过缝隙连接进行电气通信,那么统计上猝死的机会应该是 是低的,只有在大量的间隙结功能丧失后才会发生。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(触觉耦合),那么病理活动应该 在实质性的触觉重塑过程中表现出来。 此外,LQT3的症状直到青春期期间或之后才会显现,这表明年轻的 生物体通过某种与年龄相关的重塑来保护自己免受危及生命的心脏事件的侵袭。自.以来 缝隙连接重新分布在细胞周围,但不一定减少表达,缝隙连接耦合 假说充其量仍是投机性的。然而,由于细胞兴奋性和触觉的决定因素 耦合随年龄变化,触觉耦合调节钠摄取过程中猝死的假说 功能需要调查。 在成功完成这些目标后,我们将产生新的LQT3和心脏理论基础 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。
英文摘要
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.
期刊论文(4)
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会议论文
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]
通讯作者: Vrishti M. Phadumdeo;S. Weinberg
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.
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.
Arrhythmia Mechanisms Modulated by Intercalated Disc Extracellular Nanodomains
Extracellular Space as Modulator of Gap Junction-Conduction Velocity Relationship
  • 批准号:
    8207841
  • 项目类别:
  • 资助金额:
    $37.38万
  • 财政年份:
    2011
  • 负责人:
    Steven Poelzing
  • 依托单位:
Extracellular Space as Modulator of Gap Junction-Conduction Velocity Relationship
Role of the Extracellular Space as a Modulator of the Cardiac Gap Junction - Conduction Velocity Relationship
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