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Defining novel mechanisms of sudden death in Dravet syndrome: Dysregulation of sodium channels in the heart

Defining novel mechanisms of sudden death in Dravet syndrome: Dysregulation of sodium channels in the heart
定义 Dravet 综合征猝死的新机制:心脏钠通道失调
批准号:
10529313
负责人:
Przemyslaw Radwanski
金额:
$42.48万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-12-01 至 2026-11-30

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中文摘要
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英文摘要
Project Summary Sudden, unexpected death in epilepsy (SUDEP) is a fatal complication, occurring in patients with epilepsy, who were otherwise healthy. Dravet syndrome (DS), which results from a loss of function of the sodium channel (NaV) isoform NaV1.1, is associated with a particularly high risk of SUDEP. Notably, the unexpected mortality of SUDEP mirrors cases of sudden cardiac death (SCD) – unexpected death resulting from cardiac arrhythmias. Emerging evidence points to physiological commonalities between the brain and the heart, suggesting that the very molecular mechanisms that underlie epileptic disorders could also directly impact the heart, leading to life- threatening cardiac arrhythmias and thereby, SCD. However, the precise mechanisms by which DS directly impact the heart to promote cardiac arrhythmias and SCD remain unknown. Thus, we propose to utilize models of DS to address this gap in knowledge and to explore the role of direct cardiac remodeling in SCD. Using these models, we will test the hypothesis that defects in NaVs that underlie inherited epileptic disorders, such as Dravet syndrome, dysregulate cardiac Na+/Ca2+ cycling, thereby promoting life-threatening arrhythmias and contributing to SCD. Thus, we propose to: 1) Define the phenotypic and structural impacts of tissue-specific expression of DS-associated defects. 2) Determine the functional impact of DS-associated Na+/Ca2+ signaling nanodomain remodeling on cardiac Ca2+ handling. 3) Assess efficacy of targeting Na+/Ca2+ signaling nanodomains for SCD prevention. Information gleaned from these studies will be used to develop new therapeutic approaches to treat SCD in DS.
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Regulation and dysregulation of sodium channels by by calmodulin
  • 批准号:
    10475626
  • 项目类别:
  • 资助金额:
    $49.29万
  • 财政年份:
    2021
  • 负责人:
    Przemyslaw Radwanski
  • 依托单位:
Regulation and dysregulation of sodium channels by by calmodulin
  • 批准号:
    10211340
  • 项目类别:
  • 资助金额:
    $49.29万
  • 财政年份:
    2021
  • 负责人:
    Przemyslaw Radwanski
  • 依托单位:
Regulation and dysregulation of sodium channels by by calmodulin
  • 批准号:
    10673012
  • 项目类别:
  • 资助金额:
    $49.29万
  • 财政年份:
    2021
  • 负责人:
    Przemyslaw Radwanski
  • 依托单位:
Defining novel mechanisms of sudden death in Dravet syndrome: Dysregulation of sodium channels in the heart
  • 批准号:
    10366777
  • 项目类别:
  • 资助金额:
    $42.48万
  • 财政年份:
    2021
  • 负责人:
    Przemyslaw Radwanski
  • 依托单位: