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Translation initiation in cardiac intercellular communication and stress-induced remodeling

心脏细胞间通讯和应激诱导重塑中的翻译起始

基本信息

批准号：
10381442
负责人：
James William Smyth
金额：
$ 7.43万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
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 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10381442
关键词：
5&apos Untranslated Regions Animals Arrhythmia Attention Cardiac Cardiac Myocytes Cardiovascular Diseases Cause of Death Cell model Cells Code Communication Connexin 43 Coupling Data Defect Elements Event Exposure to Gap Junctions Genes Genetic Transcription Genetic Translation Goals Heart Heart Diseases Heart Hypertrophy Human Hypertrophy Hypoxia Intercalated disc Internal Ribosome Entry Site Ion Channel Ischemia Isoproterenol Knowledge Laboratories Lead Maintenance Messenger RNA Mus Myocardial Ischemia Myocardium Pathologic Pathway interactions Process Protein Biosynthesis Protein Isoforms Proteins Proteome RNA-Binding Proteins Regulation Regulatory Element Regulatory Pathway Research Ribosomes Role Slice Stress Structure System Testing Therapeutic Tissues Trans-Activators Transcript Transforming Growth Factor beta Translating Translation Initiation Translational Regulation Translations United States Viral Work base biological adaptation to stress epithelial to mesenchymal transition heart cell insight intercellular communication polypeptide prevent programs recruit sudden cardiac death

项目摘要

SUMMARY Reductions in intercellular communication occur in almost all forms of heart disease and lead to the arrhythmias of sudden cardiac death. The most intensely studied component of the intercalated disc of the working cardiomyocyte is the connexin 43 (Cx43) gap junction. The Cx43 gene, GJA1, encodes a polycistronic mRNA that undergoes internal translation events yielding truncated polypeptides capable of modulating gap junction formation and subject to altered regulation during stress such as ischemia and hypertrophy. Such internal translation within protein coding sequences of mammalian mRNAs has only recently been identified, and a substantial gap in the knowledge exists as to how this process is regulated by the cell and if manipulation of upstream regulatory pathways and associated proteins can be harnessed therapeutically to restore normal intercellular communication in diseased hearts. The objective of this application is to provide mechanistic insight into the role of altered translation initiation in pathological Cx43 gap junction regulation and remodeling. This work is significant because it will identify altered translation initiation as a common stress response in the heart and provide fundamental understanding of regulation of electrical communication through rapid alteration of the proteome by ribosomal initiation. Our central hypothesis is that dynamic regulation of the translational landscape of the cell governs intercellular communication, is vital in maintenance of proper cardiac electrical coupling, and is altered by the integrated stress response during pathological remodeling of the heart. We will test our central hypothesis with the following specific aims: AIM 1: Determine the role of altered translation initiation in gap junction regulation. The working hypothesis for this aim is that a cellular program exists at the level of translation initiation which regulates transition from a `junctional' to a `non- junctional' state. AIM 2: Delineate the regulatory elements of GJA1 mRNA critical for internal translation initiation. The working hypothesis for this aim is that GJA1 mRNA harbors sequence- and structure-based elements necessary for internal translation to occur via recruitment of specific RNA binding proteins. AIM 3: Test if modulation of translation initiation protects against pathological cardiac remodeling. Our working hypothesis for this aim is that the integrated stress response (ISR) alters translation initiation of GJA1, reducing GJA1-20k expression and limiting gap junction formation in stressed and hypertrophic myocardium. The work outlined in this proposal is significant because it will (i) provide mechanistic insight into the role of internal translation in regulation of gap junctions and intercellular communication during stress (ii) determine how this relates to pathological remodeling in hypertrophic and ischemic hearts, and (iii) test if modulation of internal translation is a viable therapeutic strategy for human heart disease.

总结

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Altered translation initiation of Gja1 limits gap junction formation during epithelial-mesenchymal transition.

DOI：
10.1091/mbc.e17-06-0406
发表时间：
2018-04-01
期刊：
Molecular biology of the cell
影响因子：
3.3
作者：
James CC;Zeitz MJ;Calhoun PJ;Lamouille S;Smyth JW
通讯作者：
Smyth JW

Adenovirus targets transcriptional and posttranslational mechanisms to limit gap junction function.

DOI：
10.1096/fj.202000667r
发表时间：
2020-07
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Calhoun PJ;Phan AV;Taylor JD;James CC;Padget RL;Zeitz MJ;Smyth JW
通讯作者：
Smyth JW

Alternative mechanisms of translation initiation: An emerging dynamic regulator of the proteome in health and disease.

DOI：
10.1016/j.lfs.2018.09.054
发表时间：
2018-11-01
期刊：
Life sciences
影响因子：
6.1
作者：
James CC;Smyth JW
通讯作者：
Smyth JW

Adenovirus transduction to express human ACE2 causes obesity-specific morbidity in mice, impeding studies on the effect of host nutritional status on SARS-CoV-2 pathogenesis.

表达人ACE2的腺病毒转导导致小鼠肥胖特异性发病率，这阻碍了宿主营养状况对SARS-COV-2发病机理的影响的研究。

DOI：
10.1016/j.virol.2021.08.014
发表时间：
2021-11
期刊：
Virology
影响因子：
3.7
作者：
Rai P;Chuong C;LeRoith T;Smyth JW;Panov J;Levi M;Kehn-Hall K;Duggal NK;Lucarelli JW
通讯作者：
Lucarelli JW

Complex I protein NDUFS2 is vital for growth, ROS generation, membrane integrity, apoptosis, and mitochondrial energetics.