权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Role of miR-574-Fam210a axis in cardiac hypertrophy and remodeling

miR-574-Fam210a 轴在心脏肥大和重塑中的作用

基本信息

批准号：
10251906
负责人：
Peng Yao
金额：
$ 38.5万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10251906
关键词：
Adrenergic Agents Adult Apoptosis Biochemical Biology Cardiac Cardiac Function Study Cardiac Myocytes Cardiac health Cardiovascular Diseases Cell Culture Techniques Cell Proliferation Coculture Techniques Development Disease Exhibits FRAP1 gene Failure Family Fibroblasts Fibrosis Gene Expression Gene Expression Regulation Genes Genetic Transcription Genetic Translation Goals Growth Heart Heart Contractilities Heart Diseases Heart Hypertrophy Heart failure Heterogeneous-Nuclear Ribonucleoprotein L Homeostasis Human Hypertrophy Impairment Injections Knock-out Knockout Mice Mediating Messenger RNA Metabolism MicroRNAs Mitochondria Mitochondrial Proteins Molecular Target Morbidity - disease rate Mus Neonatal Nuclear Nutrient Operative Surgical Procedures Pathologic Pathway interactions Phenotype Phosphorylation Play Production Protein Biosynthesis Reagent Regulation Research Resources Role Series Stress System Tamoxifen Testing Therapeutic Therapeutic Intervention Translational Regulation Translations Treatment Failure United States Untranslated RNA Ventricular Remodeling Wild Type Mouse base cardioprotection constriction coronary fibrosis exercise training exosome heart function improved in vivo insight intercellular communication member mortality mouse model novel novel therapeutics polysome profiling prevent preventive intervention protein expression protein function src-Family Kinases therapeutic target transcriptome sequencing virtual

项目摘要

Project Summary: Heart Failure (HF) results from cardiomyocyte (CM) hypertrophy and apoptosis, combined with cardiac fibroblast (CF) proliferation and fibrosis; these are hallmarks of cardiac pathological remodelling, which is accompanied by changes in the expression of specific miRNAs and mitochondrial-encoded genes (MEGs). Early stage cardiac hypertrophy (CH) induces compensatory mitochondrial protein translation. Endpoint HF is accompanied by reduced mitochondrial protein synthesis and dysfunctional mitochondria. It is generally accepted that restoring mitochondrial protein expression and function mitigates HF progression, highlighting the importance of clarifying gene regulation mechanisms in mitochondria to guide development of improved HF therapeutics. Many studies have examined mechanisms that coordinate mRNA transcription of nuclear-encoded mitochondrial genes (NEMGs) and MEGs. However, regulatory mechanisms of MEG mRNA translation and its coordination with NEMG mRNA translation in the heart remain virtually unexplored. We have identified a miR-574-Fam210a axis that maintains the optimal translation of MEGs and mitochondrial homeostasis in both CM and CF, as a compensatory cardioprotective pathway at an early stage of CH. In contrast to most other single strand miRNAs, miR-574 produces 2 functional strands, miR-574-5p and miR-574-3p. At early stage of CH, miR-574-5p antagonizes Fam210a expression in CM to prevent excessive MEG expression, enhanced ROS production and impaired mitochondrial activity, thereby preventing CM hypertrophy and apoptosis. Moreover, hypertrophic stress activates Src kinase-mediated Tyr359 phosphorylation and cytoplasmic accumulation of hnRNP L in CM. P-hnRNP L captures miR-574-3p and promotes exosome-mediated release of miR-574-3p and reduces cardiac fibroblasts (CF) proliferation by targeting CF Fam210a. Our central hypothesis is: in CM and CF, miR-574-Fam210a axis maintains optimal translation of mitochondrial-encoded genes and mitochondrial homeostasis, thereby limiting pathological cardiac hypertrophy and ventricular remodeling. We will test this hypothesis by pursuing 3 aims. Aim 1. Elucidate the mechanism of guide strand miR-574-5p in preventing pathological cardiac hypertrophy and CM apoptosis. Aim 2. Establish the role and mechanism of passenger strand miR-574-3p in antagonizing cardiac fibrosis. Aim 3. Determine the function and mechanism of Fam210a in mitochondrial translational control and regulation of cardiac function.

项目总结: