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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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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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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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