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

基本信息

  • 批准号:
    10092407
  • 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:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-07-01 至 2022-02-28
  • 项目状态:
    已结题

项目摘要

Ion channels have a plethora of functions than, frequently, can not be understood by their ability to insert in the plasma membrane and conduct ionic current. The Connexin43 (Cx43) gap junction channel, whose parent gene is GJA1, has been implicated in having a role in cell cycle progression, metastatic transformation, wound healing, development, migration, epithelial-mesenchymal transition, and metabolism. GJA1 has a single coding exon, and therefore it can not be subject to splicing and alternative transcription. However we have identified, and it has been confirmed by several laboratories, that GJA1 mRNA is subject to alternative translation in which initiation of ribosomal translation occurs not at the first AUG (Methionine) start codon, but at downstream Methionines. The result is that six additional progressive N-terminal truncation proteins (all containing the distal C- terminus) can be endogenously generated from the same mRNA molecule, which we identify by protein size (GJA1-43k for the full length protein, then GJA1-32k, GJA1-29k, GJA1-26k, GJA1-20k, GJA1-11k, and GJA1-7k). For the last three years, my group has explored the role of these smaller isoforms. This proposal is based on the application of a surprising, and frankly startling, finding regarding GJA1-20k which is usually the most highly translated of the smaller isoforms. We found that GJA1-20k has a strong tropism for mitochondria, so strong that it could function as a mitochondrial marker. Additional preliminary data indicate that GJA1-20k is protective against the stress of myocardial ischemia. Our central hypothesis is that following oxidative stress and ischemic injury, alternatively translated endogenous GJA1-20k is increased and targets to mitochondria as a myocardial survival signal. Furthermore, we will test whether exogenous GJA1-20k can reduce myocardial injury due to ischemic insult. Three specific aims are proposed. Aim #1- What is the expression, localization, and function of GJA1-20k during myocardial injury? Aim #2- Does exogenous GJA1-20k improves cardiomyocyte survival following oxidative stress? Aim #3- Does gene transfer of GJA1-20k reduce infarct size in a mouse model of myocardial ischemia? When the work in the three aims is complete, we expect to have identified critical pathways of GJA1-20k regulation during stress and have introduced a new therapeutic peptide for ischemic injury. Furthermore, we will develop the paradigm by which alternative translation is an important aspect of cardiac electrophysiology and should be applied to multiple channels as a means for understanding the mechanism of their non-canonical function.
离子通道有很多功能,通常不能通过它们的能力来理解

项目成果

期刊论文数量(20)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Letter by Nikolova et al Regarding Article, "Heart Failure With Preserved Ejection Fraction in Perspective".
Nikolova 等人关于文章“保留射血分数的心力衰竭”的信函。
  • DOI:
    10.1161/circresaha.119.315583
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    20.1
  • 作者:
    Nikolova,AndrianaP;Hong,TingTing;Shaw,RobinM
  • 通讯作者:
    Shaw,RobinM
Live-cell imaging and analysis of actin-mediated mitochondrial fission.
  • DOI:
    10.1016/j.xpro.2022.101958
  • 发表时间:
    2023-03-17
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Shimura, Daisuke;Shaw, Robin M.
  • 通讯作者:
    Shaw, Robin M.
The ESCRT-III pathway facilitates cardiomyocyte release of cBIN1-containing microparticles.
ESCRT-III途径促进了含CBIN1的微粒的心肌细胞的释放。
  • DOI:
    10.1371/journal.pbio.2002354
  • 发表时间:
    2017-08
  • 期刊:
  • 影响因子:
    9.8
  • 作者:
    Xu B;Fu Y;Liu Y;Agvanian S;Wirka RC;Baum R;Zhou K;Shaw RM;Hong T
  • 通讯作者:
    Hong T
GJA1-20k Arranges Actin to Guide Cx43 Delivery to Cardiac Intercalated Discs.
  • DOI:
    10.1161/circresaha.117.311955
  • 发表时间:
    2017-10-13
  • 期刊:
  • 影响因子:
    20.1
  • 作者:
    Basheer WA;Xiao S;Epifantseva I;Fu Y;Kleber AG;Hong T;Shaw RM
  • 通讯作者:
    Shaw RM
Cx43 Isoform GJA1-20k Promotes Microtubule Dependent Mitochondrial Transport.
  • DOI:
    10.3389/fphys.2017.00905
  • 发表时间:
    2017
  • 期刊:
  • 影响因子:
    4
  • 作者:
    Fu Y;Zhang SS;Xiao S;Basheer WA;Baum R;Epifantseva I;Hong T;Shaw RM
  • 通讯作者:
    Shaw RM
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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:
Unlocking Trafficking Specificity for Cx43 Gap Junctions
解锁 Cx43 间隙连接的贩运特异性
  • 批准号:
    10613875
  • 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:
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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由两类细菌肌动蛋白 MreB 驱动的新型运动系统
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    2000
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