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

Post-transcriptional mechanisms of gene regulation in cardiac cell growth and development

心肌细胞生长发育中基因调控的转录后机制

基本信息

批准号：
10418690
负责人：
Auinash Kalsotra
金额：
$ 38.56万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10418690
关键词：
Adult Affect Antisense Oligonucleotides Antisense RNA Binding Sites Biological Assay CRISPR/Cas technology Cardiac Cardiac Myocytes Cardiac development Cause of Death Cell Nucleus Cues Cytoplasm Development Disease Funding Gene Expression Gene Expression Regulation Gene Silencing Genetic Genetic Transcription Goals Growth Growth and Development function Heart Heart Diseases Heart Hypertrophy Heart failure Hypertrophy Knock-out Knockout Mice Laboratories Length Mediating Messenger RNA Microscopy Modeling Molecular Mus Muscle Muscle Cells Myocardial Myocardial Infarction Myocardium Neonatal Nuclear Outcome Pathologic Performance Physiological Poly A Poly(A) Tail Poly(A)-Binding Proteins Polyadenylation Polyribosomes Post-Transcriptional Regulation Protein Biosynthesis RNA RNA Splicing Regulation Regulatory Pathway Resolution Risk Factors Role Signal Transduction Skeletal Muscle Stimulus Stress Tamoxifen Testing Tetracyclines Therapeutic Tissues Trans-Activators Transcript Transgenic Mice Translating Translations United States Work cardiogenesis cell growth experimental study fetal genome editing heart function hemodynamics in vivo insight mRNA Export mouse model overexpression polysome profiling postnatal postnatal development premature programs protein expression response single molecule transcription termination transcriptome transcriptome sequencing translatome

项目摘要

I. ABSTRACT Heart disease remains the leading cause of death in the United States. Despite what we know about the risk factors associated with heart disease, the molecular mechanisms are still largely unknown. The healthy adult heart is unique from other tissues in that the rate of protein synthesis is dramatically lower than in most tissues and lower than the developing heart. However, during cardiac hypertrophy, translation rates increase. This suggests a tissue-specific mechanism for regulating translation rates in the mammalian heart. Our lab has identified a mechanism by which total protein synthesis in cardiomyocytes is decreased during development through shortening of poly(A) tails, leading to a decrease in polysome formation through the closed-loop model of translation. This regulation is reversed during both physiologic and pathologic hypertrophy when the translation needs of cardiomyocytes are increased. Also, we have discovered that the nuclear poly(A) binding protein (PABPN1) is post-transcriptionally silenced in mammalian adult cardiac and skeletal muscle but it becomes re-expressed in pathologic cardiac hypertrophy. PABPN1 is a regulator of alternative polyadenylation (APA) and poly(A) tail length, both of which can influence the translation of transcripts. Our central hypothesis is that PABPN1 is dynamically regulated in cardiac myocytes to tune translation rates and suite growth needs through a polyadenylation dependent mechanism. The objective of this proposal is to elucidate the exact function(s) of PABPN1 in cardiac development and growth and identify how PABPN1 is regulated during these conditions. Aims 1 and 2 will use conditional PABPN1-knockout and overexpressing mice to determine the physiologic roles of PABPN1 in cardiac development and hypertrophy while defining the molecular basis of PABPN1 activity and its role in determining cardiac-specific gene expression programs. In Aim 3, we will use super-resolution microscopy, CRISPR-Cas9 mediated genome editing, and RNA antisense-oligo pulldown approaches to identify the regulatory mechanism(s) and factors that post-transcriptionally silence PABPN1 during cardiac development.

即抽象