Unlocking Trafficking Specificity for Cx43 Gap Junctions

解锁 Cx43 间隙连接的贩运特异性

基本信息

  • 批准号:
    10613875
  • 负责人:
  • 金额:
    $ 38.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-04-01 至 2025-03-31
  • 项目状态:
    未结题

项目摘要

Disturbances in ion channel function is a fundamental aspect of the arrhythmias of sudden cardiac death. Recently, there has been is increased appreciation that cardiac ion channels have very short half lives, and much of disturbed ion channel function in disease results from altered trafficking and altered localization to the appropriate subdomain. Regulation of intracellular trafficking remains poorly understood for cardiac ion channels. In previous studies, we have identified how Connexin43 (Cx43) gap junction hemichannels undergo cytoskeleton based Targeted Delivery to cardiac intercalated discs. Recently, we found an endogenous truncated isoform of Cx43, the alternatively translated GJA1-20k, which is essential to full length Cx43 forward trafficking and can rescue ischemia induced defects in Cx43 gap junction localization. Our studies reveal that GJA1-20k is a critical molecule for channel and organelle movement. Understanding the molecular details of its role in cardiac muscle cells will reveal fundamental mechanisms of channel localization and also facilitate translational use of this molecule into novel and clinically important therapeutic strategies. The objective of this application is to explore the molecular mechanisms by which GJA1-20k organizes trafficking highways. Our central hypothesis is that GJA1-20k, which increases during episodes of myocardial stress, is a powerful cytoskeleton actin nucleator that builds the dynamic trafficking highways essential for Cx43 gap junction delivery. Our expertise in ion channel trafficking and identification of GJA1-20k, as well as our cell biological tools and the new mouse model we generated for this proposal, allow us to successfully carry out the planned experiments by pursuing two specific aims: 1) Is GJA1-20k essential to the formation of Cx43 gap junctions in vivo? 2) Is GJA1-20k an actin nucleator, capable of patterning cytoskeleton pathways for channel delivery? Once successfully completed, the expected outcomes are to identify that GJA1-20k is a vital cardiomyocyte protein whose mechanism of action is inherently linked to the actin and microtubule cytoskeleton, is important in baseline healthy heart, and essential during times of stress. Such results are expected to have a positive impact because we will have introduced a new therapeutic approach (exogenous GJA1-20k) to limit pathologic trafficking in arrhythmogenic disease. At the same time, and perhaps of even more long-term consequence, the studies will help resolve a fundamental unsolved mystery in the biology of protein trafficking which is how membrane proteins are delivered directly to their respective subdomain.
离子通道功能紊乱是突发性心律失常的一个基本方面, 心源性死亡最近,越来越多的人认识到心脏离子通道具有非常重要的作用。 半衰期短,疾病中许多离子通道功能紊乱是由运输改变引起的 并改变定位到适当的子域。细胞内运输的调节仍然存在 对心脏离子通道知之甚少。 在以前的研究中,我们已经确定了连接蛋白43(Cx43)是如何通过缝隙连接半通道, 进行基于细胞骨架的靶向递送至心脏闰盘。最近,我们发现了一个 Cx43的内源性截短同种型,即选择性翻译的GJA 1 - 20 k,其对于完整的 长度Cx43正向运输,并可挽救缺血诱导的Cx43间隙连接缺陷 本地化我们的研究表明GJA 1 - 20 k是通道和细胞器的关键分子 运动了解其在心肌细胞中作用的分子细节将揭示 通道定位的基本机制,并促进该分子的翻译使用 新的临床重要的治疗策略。 本申请的目的是探索GJA 1 - 20 k的分子机制 组织贩卖人口的高速公路我们的中心假设是,GJA 1 - 20 k,它在 是一种强大的细胞骨架肌动蛋白成核剂, Cx43间隙连接传递所必需的运输高速公路。 我们在离子通道运输和GJA 1 - 20 k识别方面的专业知识,以及我们的细胞 生物学工具和我们为此提议产生的新小鼠模型,使我们能够成功地携带 通过追求两个具体目标来完成计划中的实验:1)GJA 1 - 20 k对形成 Cx43间隙连接在体内?2)GJA 1 - 20 k是一种肌动蛋白成核剂,能够形成细胞骨架吗 渠道交付的途径? 一旦成功完成,预期的结果是确定GJA 1 - 20 k是一个至关重要的 一种心肌细胞蛋白质,其作用机制与肌动蛋白和微管有内在联系 细胞骨架在基线健康心脏中是重要的,并且在压力期间是必不可少的。这样的结果 因为我们将引入一种新的治疗方法, (外源性GJA 1 - 20 k)以限制致瘤性疾病中的病理性运输。的同时 也许更长远的后果,这些研究将有助于解决一个根本的悬而未决的问题, 蛋白质运输生物学中的一个谜团,即膜蛋白如何直接运送到 各自的子域名。

项目成果

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Robin M Shaw其他文献

Robin M Shaw的其他文献

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{{ truncateString('Robin M Shaw', 18)}}的其他基金

Unlocking Trafficking Specificity for Cx43 Gap Junctions
解锁 Cx43 间隙连接的贩运特异性
  • 批准号:
    10377923
  • 财政年份:
    2020
  • 资助金额:
    $ 38.13万
  • 项目类别:
A New Non-Canonical Role for an Alternatively Translated Ion Channel Protein
替代翻译的离子通道蛋白的新非典型作用
  • 批准号:
    9376618
  • 财政年份:
    2017
  • 资助金额:
    $ 38.13万
  • 项目类别:
A New Non-Canonical Role for an Alternatively Translated Ion Channel Protein
替代翻译的离子通道蛋白的新非典型作用
  • 批准号:
    10092407
  • 财政年份:
    2017
  • 资助金额:
    $ 38.13万
  • 项目类别:
Novel Mechanisms of Cardiac Ion Channel Regulation
心脏离子通道调节的新机制
  • 批准号:
    8823481
  • 财政年份:
    2009
  • 资助金额:
    $ 38.13万
  • 项目类别:
Gap Junction Trafficking to and within the Plasma Membrane
间隙连接运输到质膜和质膜内
  • 批准号:
    7661737
  • 财政年份:
    2009
  • 资助金额:
    $ 38.13万
  • 项目类别:
Novel Mechanisms of Cardiac Ion Channel Regulation
心脏离子通道调节的新机制
  • 批准号:
    8966027
  • 财政年份:
    2009
  • 资助金额:
    $ 38.13万
  • 项目类别:
Gap Junction Trafficking to and within the Plasma Membrane
间隙连接运输到质膜和质膜内
  • 批准号:
    8706447
  • 财政年份:
    2009
  • 资助金额:
    $ 38.13万
  • 项目类别:
Gap Junction Trafficking to and within the Plasma Membrane
间隙连接运输到质膜和质膜内
  • 批准号:
    7806535
  • 财政年份:
    2009
  • 资助金额:
    $ 38.13万
  • 项目类别:
Gap Junction Trafficking to and within the Plasma Membrane
间隙连接运输到质膜和质膜内
  • 批准号:
    8043581
  • 财政年份:
    2009
  • 资助金额:
    $ 38.13万
  • 项目类别:
Gap Junction Trafficking to and within the Plasma Membrane
间隙连接运输到质膜和质膜内
  • 批准号:
    8443871
  • 财政年份:
    2009
  • 资助金额:
    $ 38.13万
  • 项目类别:

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炎症在心房颤动发病机制中的作用:对心房重塑病理生理学以及射频消融和脉冲场消融后早期房性心律失常复发的影响
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