Reversal of Heart Failure: Role of Vascular Recovery

逆转心力衰竭：血管恢复的作用

基本信息

批准号：
10602443
负责人：
JOHN P COOKE
金额：
$ 71.09万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
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：
2020-07-15 至 2024-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10602443
关键词：
Acetyl Coenzyme A Adult Affect Animal Model Area Bioinformatics Biological Biological Assay Blood Vessels Blood capillaries Candidate Disease Gene Cardiac Cell Lineage Cell Nucleus Cell physiology Cells Cicatrix Citrates Clinical Clinical Data Collagen Complement Computer Models Coupled DNA Data Device Removal Diastolic blood pressure Direct Costs Echocardiography Endothelial Cells Endothelium Enhancers Epigenetic Process Fibroblasts Fibrosis Gene Expression Profiling Genes Genetic Determinism Health Care Costs Heart Heart failure Histologic Histone Acetylation Human Impairment In Vitro Intercellular Fluid International Knock-out Left Ventricular Mass Libraries Lung Mediating Mesenchymal Mesenchymal Differentiation Metabolic Metabolic Pathway Metabolism Methods Microspheres Mitochondria Modeling Modification Molecular Morbidity - disease rate Mus Muscle Cells Myocardial Natural regeneration Pathologic Pathway interactions Patients Pattern Perfusion Perivascular Fibrosis Physiological Population Process Recovery Research Reverse Transcriptase Polymerase Chain Reaction Role Sampling Services Specimen System Time Tissues Transgenic Mice Transplantation Vascular regeneration Ventricular Ventricular Function Work Workload coronary fibrosis density epigenetic regulation heart function hemodynamics human tissue implantation improved in vivo insight interstitial knock-down left ventricular assist device loss of function mortality mouse model novel novel therapeutic intervention novel therapeutics pre-clinical promoter public database single-cell RNA sequencing small hairpin RNA small molecule inhibitor transcriptome sequencing transdifferentiation

项目摘要

PROJECT SUMMARY Heart failure is a major cause of morbidity and mortality worldwide, currently affecting an estimated 6.5 million adults in the US alone and contributing to $21 billion in health care costs. The aim of this proposal is to understand the mechanisms of heart failure recovery. We have clinical evidence that heart failure recovery involves a reduction in interstitial myocardial fibrosis and an increase in microvascular density. Our library of human samples from Left Ventricular Assist Device (LVAD) implantation/explantation represent a convenience sample to examine the mechanisms of recovery. In these patients, the LVAD implantation (and unloading of the heart from hemodynamic forces) promotes some improvement in ventricular function (as assessed by echocardiography) that is associated with decreased interstitial fibrosis and increased vascular density. Based on clinical and pre-clinical data, we hypothesize that recovery from heart failure is (at least in part) a vascular recovery. The vascular recovery may involve mesenchymal-to-endothelial transition (MEndoT), that is, the transdifferentiation of cardiac fibroblasts (or other mesenchymal cells) into endothelial cells. Furthermore, we have evidence that MEndoT may require a glycolytic switch that directly affects DNA accessibility and cellular plasticity. In our first aim, we will characterize the physiological, cellular, and molecular hallmarks of heart failure recovery in a unique mouse model. In the second aim, transcriptional profiling of disaggregated mouse hearts as well as human cardiac tissue obtained pre- and post-LVAD implantation will be combined with bioinformatics analyses to predict novel genes in heart failure recovery. In our third aim, we will confirm the genetic determinants discovered in the first aim using gain- or loss-of-function studies in vitro and in vivo. In addition, we will explore the role of the glycolytic switch in cell fate transitions and vascular recovery using bioinformatics analyses of our RNAseq data, confirmed with cell-specific and conditional gain- or loss-of-function studies of target genes (e.g. in metabolic pathways) in vitro and in vivo. The intent of this proposal is to generate fundamental insights regarding heart failure recovery that may lead to a new therapeutic strategy.

项目摘要心力衰竭是全球发病率和死亡率的主要原因，目前估计有650万仅美国的成年人，贡献了210亿美元的医疗保健费用。该提议的目的是了解心力衰竭恢复的机制。我们有临床证据表明心力衰竭恢复涉及间质心肌纤维化的降低和微血管密度的增加。我们的人类图书馆左心室辅助装置（LVAD）植入/膨胀的样品代表便利样本检查恢复机制。在这些患者中，LVAD植入（和心脏卸载从血液动力学中）促进了心室功能的一些改善（如超声心动图）与间隙纤维化降低和血管密度增加有关。基于临床和临床前数据，我们假设从心力衰竭中恢复（至少部分）是血管恢复。血管恢复可能涉及间质向内皮转变（Mendot），即心脏成纤维细胞（或其他间质细胞）转差为内皮细胞。此外，我们有证据表明门多特可能需要直接影响DNA可及性和细胞的糖酵解开关可塑性。在我们的第一个目标中，我们将表征心力衰竭的生理，细胞和分子标志在唯一的鼠标模型中恢复。在第二个目标中，分解小鼠心脏的转录分析为以及在LVAD前和LVAD植入后获得的人类心脏组织将与生物信息学结合分析以预测心力衰竭恢复中的新基因。在我们的第三个目标中，我们将确认遗传在第一个目标中发现了使用体外和体内功能丧失研究发现的决定因素。此外，我们将探索使用生物信息学的糖酵解开关在细胞命运过渡和血管恢复中的作用通过细胞特异性和条件增益或功能丧失研究证实，我们的RNASEQ数据的分析靶基因（例如，在代谢途径中）在体外和体内。该提议的目的是生成关于心力衰竭恢复的基本见解，可能导致新的治疗策略。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cardiac Shockwave Therapy - A Novel Therapy for Ischemic Cardiomyopathy?

DOI：
10.3389/fcvm.2022.875965
发表时间：
2022
期刊：
Frontiers in cardiovascular medicine
影响因子：
3.6
作者：
通讯作者：

Vascular senescence in progeria: role of endothelial dysfunction.

DOI：
10.1093/ehjopen/oeac047
发表时间：
2022-07
期刊：
European heart journal open
影响因子：
0
作者：
Xu, Qiu;Mojiri, Anahita;Boulahouache, Luay;Morales, Elisa;Walther, Brandon K;Cooke, John P
通讯作者：
Cooke, John P

Future Impact of mRNA Therapy on Cardiovascular Diseases.