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Alternative protein isoforms in ventricular remodeling

心室重构中的替代蛋白质亚型

基本信息

批准号：
10391342
负责人：
Maggie Lam
金额：
$ 38.91万
依托单位：
UNIVERSITY OF COLORADO DENVER
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：
2018-06-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10391342
关键词：
Adult Affinity Chromatography Aging Alternative Splicing Amino Acid Sequence Biological Assay Biological Phenomena Cardiac Cardiovascular Diseases Cardiovascular system Cell Death Cell Death Process Code Coupled Data Detection Development Disease Disease Progression Event Exons Foundations Genes Genetic Genome Goals Guide RNA Health Heart Heart Diseases Heart Hypertrophy Human Hypertrophy In Vitro Isoproterenol Knowledge Level of Evidence Malignant Neoplasms Mass Spectrum Analysis Messenger RNA Metabolic Metabolism Modeling Molecular Muscle Cells Myocardial Infarction Myocardial Ischemia Myocardium Neonatal Oxygen Pathogenesis Pathology Pattern Perinatal Phenotype Positioning Attribute Protein Isoforms Proteins Proteome Proteomics RNA Splicing Rattus Regulation Research Resolution Role Sampling Science Severities Techniques Technology Transcript Translating Ventricular Ventricular Remodeling crosslink differential expression fetal heart function in silico ischemic injury knock-down molecular sequence database mouse model multiple omics novel strategies overexpression programs protein function protein protein interaction ribosome profiling screening skeletal therapeutic target tool transcriptome transcriptome sequencing transcriptomics virtual

项目摘要

PROJECT SUMMARY Many cardiac genes undergo alternative splicing to produce cardiac vs. skeletal, and adult vs. fetal isoforms. Differential regulation of alternative splicing patterns is a central component of the altered genetic program during cardiac remodeling after ischemic injuries. Alternative splicing has been shown to causally modulate the severity of cardiac remodeling, and thus represents a potential therapeutic target to halt disease progression. Nevertheless, although a large number of alternative isoform transcripts have now been discovered in the cardiac genome, current knowledge on the protein coding potential and hence molecular functions of these alternative isoform is poor. The majority of discovered isoforms were yet to be detected at the protein level -- therefore the effects of alternative isoforms on protein abundance, motif features, and protein-protein interactions are virtually unknown. This knowledge gap obstructs a fuller understanding on the impact of alternative splicing on the myocardium in health and disease. Proteomics technologies have advanced in recent years and are now well positioned to transform cardiovascular sciences, but the detection of isoform proteins remains a substantial challenge. We and others have recently shown that transcriptomics (RNA-seq) and proteomics (mass spectrometry) data may be combined to probe more deeply into the cardiac proteome. In this project, we will combine the respective strengths of RNA-seq (modeling transcript isoforms) and proteomics (providing protein-level evidence) to examine cardiac alternative splicing. Specifically, we will apply this RNA-seq-guided- proteomics approach to: (i) define the landscape of alternative protein isoforms in fetal and adult hearts; (ii) identify disease signature isoforms in remodeling hearts using mouse models of myocardial infarction and isoproterenol stimulation; (iii) examine the functional consequence of protein isoforms by identifying isoform- specific protein-protein interactions and modulators of isoform expression in disease; and (iv) elucidate the impact of isoform-specific overexpression/knockdown on myocyte functional phenotypes. We anticipate the completion of the proposed studies will open new avenues into understanding the role of alternative splicing in heart diseases.

项目总结