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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：
Robin M Shaw
金额：
$ 38.13万
依托单位：
UNIVERSITY OF UTAH
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

来源：
https://reporter.nih.gov/project-details/10092407
关键词：
Accounting Actins Adenoviruses Adult Arrhythmia Biological Biological Process Biology C-terminal Cardiac Cardiac Electrophysiologic Techniques Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cause of Death Cell Communication Cell Cycle Progression Cell Maintenance Cell Survival Cell membrane Cells Cessation of life Charge Code Connexin 43 Connexins Consumption Critical Pathways Data Development Disease Distal Epithelial Epithelium Exons Failure Gene Transfer Genes Genetic Transcription Goals Heart Heart failure Hydrogen Peroxide Infarction Initiator Codon Injury Intercalated disc Ion Channel Ion Channel Protein Ischemia Laboratories Length Mediating Mesenchymal Messenger RNA Metabolism Methionine Mitochondria Modeling Morbidity - disease rate Movement Mus Myocardial Myocardial Ischemia Myocardium N-terminal Organelles Outcome Oxidative Stress Parents Pathogenesis Pathologic Peptides Phenotype Process Protein Isoforms Protein Truncation Proteins RNA Splicing Regulation Reperfusion Therapy Research Ribosomes Role Science Signal Transduction Stress Tail Testing Therapeutic Transcript Translating Translations Tropism United States United States National Institutes of Health Ventricular Work base cardioprotection gap junction channel gene therapy heart function improved in vivo ischemic injury migration mortality mouse model myocardial injury new therapeutic target novel therapeutic intervention novel therapeutics peptide drug preservation sudden cardiac death targeted delivery therapeutic development tool trafficking wound healing

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