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

Role of GPNMB in cardiac remodeling

GPNMB 在心脏重构中的作用

基本信息

批准号：
10521279
负责人：
Arjun Deb
金额：
$ 68.8万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-20 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10521279
关键词：
Acute myocardial infarction Adopted Affect Antisense Oligonucleotides Attenuated Binding Biological Biological Markers Biological Models Biology Bone Marrow Transplantation Cardiac Cardiac Myocytes Cardiovascular Agents Cells Cicatrix Circulation Collaborations Data Dependovirus Development Diagnosis Dilatation - action Event Extracellular Domain Extracellular Matrix Fibroblasts Fibrosis GPR39 gene Genes Genetic Glycoproteins Heart Heart Hypertrophy Heart Injuries Heart failure Heparitin Sulfate Human Human Genetics Hypertrophy Inbred Strains Mice Infarction Injury Integral Membrane Protein Isoproterenol Ligand Binding Macrophage Maps Mediating Mitochondria Mus Muscle Cells Myocardial Infarction Myocardium Natural regeneration Nonmetastatic Orphan Pathway interactions Peptide Hydrolases Pharmacologic Substance Physiological Physiology Plasma Proteins Proteomics Public Health Role Signal Pathway Site-Directed Mutagenesis Source System Therapeutic Time Tissues Wild Type Mouse attenuation experimental study gain of function genetic approach healing heart function heart preservation hemodynamics in vivo insight loss of function melanoma mouse genetics mouse model multidisciplinary novel pharmacologic pressure protein B receptor recruit repaired response trait wound healing

项目摘要

PROJECT SUMMARY/ABSTRACT The mammalian heart has a poor ability to regenerate heart muscle following myocardial infarction and dead cardiac muscle is replaced by scar tissue. Scar tissue is non-contractile, induces adverse cardiac remodeling and leads to dilatation of cardiac chambers, cardiomyocyte hypertrophy and development of heart failure. Despite optimal use of cardiovascular drugs, adverse remodeling following myocardial infarction contributes to 40% of all new case of heart failure. There thus exists an immense need to identify new targets for attenuating post infarct remodeling and development of heart failure. In this application, we identify GPNMB (Glycoprotein Non-Metastatic Melanoma Protein B) as a novel target for attenuating post infarct cardiac remodeling. We identified the protein using a systems genetics approach, in which a panel of inbred strains of mice were studied for heart failure traits in response to isoproterenol treatment. We demonstrate that GPNMB expression increases by an order of magnitude in infarcted murine hearts and regulates wound healing events in the heart early following injury. We show that macrophages that are recruited to the infarcted heart are the primary source of GPNMB expression. Using loss and gain of function approaches, we demonstrate that GPNMB activates cardiac fibroblasts and induces profound cardiomyocyte hypertrophy. In contrast, genetic deletion of GPNMB leads to attenuation of post infarct cardiac remodeling and is associated with better preservation of cardiac function. We also provide data that GPNMB plasma levels in humans is strongly associated with heart failure strengthening a causal relationship between GPNMB and the development of post infarct heart failure. Considering these observations, we hypothesize that GPNMB regulates (i) post infarct cardiac remodeling and (ii) inhibition of GPNMB will attenuate post infarct cardiac remodeling. We have assembled a multi-disciplinary team comprising expertise in cardiac physiology, genetics and extracellular matrix biology to interrogate the role and mechanisms of GPNMB in regulating post infarct cardiac remodeling. In the first aim, we will examine the role of GPNMB on cardiac remodeling with gain and loss of function approaches. In the second aim, we will identify mechanisms of GPNMB activation and use physico-chemical studies to determine the receptor to which GPNMB ligand binds and GPNMB domains critical for binding. In the third aim, we will use mouse and human genetics approaches to model biological pathways influenced by GPNMB and interrogate common downstream signaling pathways that mediate GPNMB effects on myocytes and non-myocytes. Finally, we will determine whether pharmacological targeting of GPNMB can be therapeutic strategy for attenuating adverse remodeling after cardiac injury.

项目总结/文摘