The Role of Junctophilin Type 2 in Cardiac Node Automaticity

2 型亲结蛋白在心脏结自律性中的作用

基本信息

  • 批准号:
    9294240
  • 负责人:
  • 金额:
    $ 15.39万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-04-04 至 2022-03-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT Diseases of the nodal tissue of the heart can be life threatening, particularly in the young. Nodal tissue spontaneously depolarizes serving as a pacemaker for cardiac contraction, yet despite this central role critical for survival, the cause of nodal dysfunction is poorly understood. This lack of mechanistic understanding has impaired development of efficacious and selective pharmacotherapies, and as a correlate, drugs levied against nodal disease carry significant toxicity for the patient and can still be entirely ineffective. While the nodal automaticity was traditionally thought to be controlled by ion channels on the plasma membrane, there is a growing body of evidence that calcium-signaling within the cell may regulate spontaneous depolarization – its automaticity. Previous investigation has shown that calcium leak from the internal calcium release channel, RyR2, may be associated with increased nodal firing, thus understanding this so-called “calcium clock” can provide additional molecular targets for nodal-specific novel therapeutics. I have created a mouse model of nodal-specific expression silencing of a protein called junctophilin-2 (JPH2), which I have previously shown to be critical to effective calcium- handling in the contractile myocyte, as a tool for studying a dysfunctional calcium clock. I have found that this mouse has an elevated heart rate at rest and a rapidly firing atrioventricular node which causes an arrhythmia known as accelerated junctional rhythm (AJR). I propose 3 specific aims to test our central hypothesis that reduced JPH2 expression results in CaMKII-mediated increase in RyR2 gating which causes increased store calcium leak and drives increased nodal automaticity and AJR. My aims are to 1) utilize confocal-based calcium imaging of isolated nodal cells from HCN4:shJPH2 mice, coupled with RyR2 single channel recordings to determine whether reduced JPH2 expression causes increased calcium leak with higher RyR2 channel opening probability; 2) apply known chemical inhibitors of RyR2 to isolated single cells and HCN4:shJPh2 mice to assess whether calcium leak can be normalized and AJR effectively treated; and 3) conduct biochemistry from isolated nodal tissue to determine the role of CaMKII signaling, including its downstream phosphorylation targets, in regulation of nodal firing. I expect that completion of these aims will yield clinically translatable mechanistic insight into the “calcium clock” of the node. Through exploration of the first murine model of isolated cardiac nodal disease in the literature, these aims will provide a substrate from which to test novel therapeutic agents specifically targeted at perturbed calcium-signaling in nodal tissue. Completion of this 5-year training grant will allow me to combine my clinical training in pediatric electrophysiology with exploration of the molecular mechanisms of nodal disease and become an independently funded physician-scientist committed to helping children with arrhythmias.
抽象的 心脏淋巴结组织的疾病可能会威胁生命,尤其是在年轻人中。淋巴结组织 赞助将作为心脏收缩起搏器的起搏器去极化,但目的地这个中心作用 对于生存至关重要的是,淋巴结功能障碍的原因知之甚少。缺乏机械 理解损害了有效和选择性药物治疗的发展,并 相关的是,针对淋巴结疾病征收的药物对患者具有明显的毒性,仍然可以是 传统上认为节点自动化是由离子控制的 质膜上的通道,越来越多的证据表明钙信号在 细胞可能调节赞助的去极化 - 自动化。以前的调查表明 内部钙释放通道RYR2的钙泄漏可能与淋巴结增加有关 发射,因此理解这种所谓的“钙时钟”可以为 淋巴结特异性的新型疗法。我创建了一个鼠标特异性表达沉默的鼠标模型 一种称为联合蛋白-2(JPH2)的蛋白质,我以前证明对有效钙至关重要 在收缩肌细胞中处理,作为研究功能障碍钙时钟的工具。我找到了 该鼠标的静止心率升高,并且迅速触发的房屋淋巴结引起 心律不齐,称为加速连接节律(AJR)。我提出了3个特定目标,以测试我们的 降低JPH2表达的中心假设导致CAMKII介导的RYR2门控的增加 这会导致钙泄漏增加,并驱动淋巴结自动化和AJR。我的目标 到1)利用来自HCN4的分离淋巴结细胞的基于共聚焦的钙成像:SHJPH2小鼠,耦合 使用RYR2单信道记录来确定降低的JPH2表达是否增加 钙泄漏具有较高的RYR2通道打开概率; 2)应用RYR2的已知化学抑制剂 孤立的单细胞和HCN4:SHJPH2小鼠,以评估是否可以将钙泄漏标准化,并且 AJR有效治疗; 3)从分离的淋巴结组织进行生物化学来确定 CAMKII信号传导,包括其下游磷酸化靶标,以调节结节射击。我希望 这些目标的完成将产生对“钙时钟”的临床翻译机械洞察力 节点。通过探索第一个孤立心脏疾病的鼠模型 文献,这些目的将提供一个基材,从中可以从中专门测试新型热剂 针对淋巴结组织中的钙信号。完成这项为期5年培训补助金将允许 我将小儿电生理学中的临床培训与分子的探索结合 结节疾病的机制,并成为致力于的独立资助的身体科学家 帮助心律不齐的孩子。

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Andrew P. Landstrom其他文献

CARDIOVASCULAR DISEASE RISK FACTORS IN CHILDREN AND ADULTS WITH CONGENITAL HEART DISEASE ARE ASSOCIATED WITH HEART FAILURE: A POPULATION-BASED MULTI-SITE CROSS SECTIONAL ANALYSIS
  • DOI:
    10.1016/s0735-1097(21)01799-x
  • 发表时间:
    2021-05-11
  • 期刊:
  • 影响因子:
  • 作者:
    Andrew P. Landstrom;Tracy Spears;Alfred D’Ottavio;Karen Chiswell;Kristin Sommerhalter;Aida Soim;Sherry Farr;Tessa Crume;Wendy Book;Kevin Whitehead;Lorenzo Botto;Jennifer Li;Daphne Hsu
  • 通讯作者:
    Daphne Hsu
EN-452411-1 <strong><em>DISCOVARI</em>: A WEB-BASED PRECISION MEDICINE TOOL FOR PREDICTING VARIANT PATHOGENICITY IN CARDIOMYOPATHY- AND CHANNELOPATHY-ASSOCIATED GENES</strong>
  • DOI:
    10.1016/j.hrthm.2023.03.409
  • 发表时间:
    2023-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Leonie M. Kurzlechner;Sujata Kishnani;Shawon Chowdhury;Sage Atkins;Lauren Parker;Michael B. Rosamilia;Hanna Tadros;Leslie Pace;Viraj Patel;Anwar A.A. Chahal;Andrew P. Landstrom
  • 通讯作者:
    Andrew P. Landstrom
<strong>Early clinical phenotype of late-onset Pompe disease: Lessons learned from newborn screening</strong>
  • DOI:
    10.1016/j.ymgme.2021.11.141
  • 发表时间:
    2022-02-01
  • 期刊:
  • 影响因子:
  • 作者:
    Erin Huggins;Maggie Holland;Laura E. Case;Janet Blount;Andrew P. Landstrom;Harrison N. Jones;Priya S. Kishnani
  • 通讯作者:
    Priya S. Kishnani
LMNA Cardiomyopathy: Important Considerations for the Heart Failure Clinician.
LMNA 心肌病:心力衰竭临床医生的重要考虑因素。
  • DOI:
    10.1016/j.cardfail.2023.08.016
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    6
  • 作者:
    K. F. Rosario;Ravi Karra;Kaitlyn Amos;Andrew P. Landstrom;N. Lakdawala;Kyla Brezitski;Han W. Kim;A. DeVore
  • 通讯作者:
    A. DeVore
A Novel Mutation in <em>TNNC1-</em>ENCODED Cardiac Troponin C Predisposes to Hypertrophic Cardiomyopathy and Recurrent Episodes of Aborted Sudden Cardiac Death
  • DOI:
    10.1016/j.bpj.2010.12.832
  • 发表时间:
    2011-02-02
  • 期刊:
  • 影响因子:
  • 作者:
    Michelle S. Parvatiyar;Andrew P. Landstrom;Jose Renato Pinto;Jingsheng Liang;Michael J. Ackerman;James D. Potter
  • 通讯作者:
    James D. Potter

Andrew P. Landstrom的其他文献

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{{ truncateString('Andrew P. Landstrom', 18)}}的其他基金

Determining the genetic and social determinants of heart failure and mortality in patients with congenital heart disease
确定先天性心脏病患者心力衰竭和死亡率的遗传和社会决定因素
  • 批准号:
    10735690
  • 财政年份:
    2023
  • 资助金额:
    $ 15.39万
  • 项目类别:
Exploring the role of ATP1A3 mutations in sudden unexplained death in epilepsy
探索 ATP1A3 突变在癫痫不明原因猝死中的作用
  • 批准号:
    10522820
  • 财政年份:
    2022
  • 资助金额:
    $ 15.39万
  • 项目类别:
Exploring the role of ATP1A3 mutations in sudden unexplained death in epilepsy
探索 ATP1A3 突变在癫痫不明原因猝死中的作用
  • 批准号:
    10688211
  • 财政年份:
    2022
  • 资助金额:
    $ 15.39万
  • 项目类别:
The Role of Junctophilin Type 2 in Cardiac Node Automaticity
2 型亲结蛋白在心脏结自律性中的作用
  • 批准号:
    10178073
  • 财政年份:
    2018
  • 资助金额:
    $ 15.39万
  • 项目类别:

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