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Smyd1's role in regulating disease-induced remodeling and gene expression in the cardiomyocyte

Smyd1 在调节疾病诱导的心肌细胞重塑和基因表达中的作用

基本信息

批准号：
9790933
负责人：
Marta Szulik
金额：
$ 6.77万
依托单位：
UNIVERSITY OF UTAH
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 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9790933
关键词：
Address Adult Affect American Animal Model Attenuated Binding Cardiac Cardiac Myocytes Cardiac development Cause of Death Cessation of life Chromatin Chromatin Remodeling Factor Chromatin Structure DNA DNA sequencing Data Developed Countries Developing Countries Disease Disease Progression Epigenetic Process Evaluation Excision Fibrosis Functional disorder Future Gene Activation Gene Expression Gene Expression Regulation Gene Silencing Gene-Modified Genes Genetic Transcription Genome Genomics Global Change Growth Heart Heart Diseases Heart Hypertrophy Heart failure Histone Deacetylase Inhibitor Histones Human Hypertrophy Lysine Methylation Modification Molecular Morphology Mus Muscle Cells Myocardium Nature Organ Pathologic Pathology processes Patients Phenotype Phenylephrine Physiology Play Post-Translational Protein Processing Protein Isoforms Proteins Role Signal Pathway Signal Transduction Stress Structure Therapeutic Therapeutic Intervention Transgenic Mice Variant Work Workload blood pump cardiogenesis cell growth chromatin immunoprecipitation chromatin remodeling combat epigenetic regulation experimental study fetal functional decline genome-wide heart function histone demethylase histone methyltransferase histone modification inhibitor/antagonist mouse model next generation novel overexpression prevent programs protein expression tool

项目摘要

Project Summary Heart failure is the leading cause of death in developed countries and is characterized by myocyte growth, fibrosis and organ remodeling, and is accompanied by transcriptional changes in the myocyte genome. These global changes in gene expression, which constitute both adaptive and maladaptive reprogramming, are driven by structural changes in chromatin. Although many epigenetic factors have been identified that influence these transcriptional changes, the proteins responsible for regulating chromatin and their subsequent effects on cellular and organ remodeling during heart disease are largely unknown. One key mechanism to alter chromatin structure is through histone modifications and early studies utilizing histone deacetylase inhibitors revealed that heart disease progression could be attenuated upon treatment in animal models, although the ubiquitous expression of these proteins and the non-specific nature of the inhibitors has made them unfeasible as a therapeutic tool in the heart, thus far. In contrast, Smyd1, is a unique myocyte-specific histone methyltransferase that regulates gene expression in the cardiomyocyte. It was originally shown to play a role in early cardiac development, however more recently, we have determined that Smyd1 is differentially regulated in human heart failure patients and in mouse models of heart disease. In addition, we have demonstrated that loss of Smyd1 in the adult mouse heart leads to pro-hypertrophic signaling resulting in myocyte growth, fibrosis and functional decline. Additionally, we examined the two Smyd1 isoforms, Smyd1a and Smyd1b, in isolated myocytes and showed that Smyd1a overexpression was capable of inhibiting phenylephrine-induced hypertrophy. To build upon this work I will (Aim 1) determine if overexpression of Smyd1a in the heart is able to inhibit disease-induced remodeling using a novel transgenic mouse model, and (Aim 2) identify the specific genes modified by Smyd1 in the genome to regulate hypertrophic signaling in the myocardium using chromatin immunoprecipitation and next-generation DNA sequencing (ChIP-Seq). This proposal will allow me to determine the function of Smyd1 in the adult heart, evaluate its role in attenuating heart disease and identify the molecular mechanisms by which myocyte growth is regulated. Overall these experiments will enhance our understanding of how global changes in chromatin remodeling are coordinated and how they affect cardiac phenotype during the development of heart disease.

项目总结