Transcription Factor 4 Maintain Endothelial identity to Oppose Heart Failure

转录因子 4 维持内皮特性以对抗心力衰竭

• 批准号: 10366197
• 负责人: Lili Zhang
• 金额: $ 50.17万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-10 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366197
• 关键词: Angiotensin II; Attenuated; Bioinformatics; Biological Assay; Cardiac; Cells; Chronic; Coculture Techniques; Communication; Computer Models; Coronary artery; Data; Diastolic blood pressure; Down-Regulation; Endothelial Cells; Endothelium; Enhancers; Epigenetic Process; Exhibits; Fibroblasts; Fibrosis; Foundations; Functional disorder; Gene Expression; Gene Silencing; Genes; Genetic; Genomics; Heart; Heart failure; Impairment; In Vitro; Incidence; Infusion procedures; Intercellular Fluid; Knowledge; Literature; Lung; Maintenance; Mediating; Mesenchymal; Modeling; Molecular; Morbidity - disease rate; Myocardial; Myofibroblast; Nature; Outcome; PF4 Gene; Pathway interactions; Patients; Performance; Phenotype; Play; Proteins; Reporting; Role; System; T cell factor 4; TCF Transcription Factor; Testing; Therapeutic; Time; Tissues; Transforming Growth Factor beta; Vasodilation; Ventricular; Work; autocrine; cell type; coronary fibrosis; density; endothelial dysfunction; epithelial to mesenchymal transition; gene discovery; histone modification; in vivo Model; insight; intercellular communication; interstitial; loss of function; machine learning model; mortality; novel; overexpression; paracrine; prevent; targeted treatment; transcription factor; transdifferentiation

Project Summary Heart failure (HF) has a high morbidity and mortality. Its incidence is increasing worldwide. One hallmark of HF is endothelial cell (EC) dysfunction which initially manifests as impaired endothelium-dependent vasodilation of the epicardial coronary arteries and the microvasculature. Another important hallmark of HF is the presence of interstitial fibrosis, which increases myocardial stiffness and cardiac work, elevates diastolic pressures and increases pulmonary interstitial fluid to impair oxygenation. Genetic lineage tracing showed that most HF fibroblasts originate from tissue-resident fibroblasts, which expand and differentiate into myofibroblasts. However, the molecular mechanisms regulating fibroblast activation and myofibroblast transdifferentiation remain poorly understood. Intercellular communication, especially EC-fibroblast crosstalk, plays a substantial modulatory role in the normal and failing heart. More specifically, factors secreted by cardiac microvascular EC modulate cardiac performance and cardiac fibrosis. Thus, targeting endothelial dysfunction has the potential to be a promising therapeutic avenue for HF. Recently, we and other groups discovered that genes important for the control of cell identity exhibit a unique epigenetic signature, e.g., broad enrichment of the activating histone modification H3K4me3 and super- enhancer marks. These discoveries prompted our pilot work to develop the first computational model for the discovery of new EC master regulators. This novel model employs an analysis of both the epigenetic landscape as well as the gene expression network. It successfully recaptured known EC identity genes with high sensitivity and accuracy. The model further revealed a number of top ranked genes with no reported role in EC, making them promising candidates as novel EC identity genes. One of the most top-ranked genes is transcription factor 4 (TCF4), which displays typical features of cell identity gene in EC. Interestingly, we have preliminary data showing that TCF4 function is a master regulator that maintains EC identity. Further, TCF4 is downregulated in cardiac ECs of HF patients compared to non-failing controls. The silencing of TCF4 in EC leads to an increase of EC-secreted proteins TGFβ1, which stimulate fibroblast activation and myofibroblasts transdifferentiation, and thus promote cardiac fibrosis. In this proposal, we will investigate the role of TCF4 in EC identity maintenance. We will further investigate the role of TCF4 in the crosstalk between ECs and fibroblasts, and reveal TCF4 as a therapy target to prevent cardiac fibrosis in HF. Successful completion of this proposal will be the first to define TCF4 as a novel EC master regulator that maintains EC phenotype and function. We will uncover an overlooked determinant of HF -- loss of EC identity. TCF4 dysregulation disturbs EC-fibroblast crosstalk within the heart, aggravating cardiac fibrosis in HF. Therapeutic modulation of EC-specific TCF4 delivery may be a novel and promising approach for treating HF.

项目摘要 心力衰竭（HF）具有高发病率和死亡率。它的发病率在全球范围内增加。一个标志 HF是内皮细胞（EC）功能障碍，最初表现为受损的内皮依赖性 心外膜冠状动脉和微脉管系统的血管舒张。 HF的另一个重要标志是 增加心肌僵硬和心脏作用的间质纤维化的存在可升高舒张期 压力并增加肺间隙液以损害氧合。遗传谱系追踪表明 大多数HF成纤维细胞源自组织居住的成纤维细胞，它们扩展并分化为 肌纤维细胞。但是，调节成纤维细胞激活和成肌纤维细胞的分子机制 转变的理解仍然很差。细胞间交流，尤其是EC纤维细胞串扰， 在正常和失败的心脏中起着重要的调节作用。更具体地，由 心脏微血管EC调节心脏性能和心脏纤维化。那是针对内皮的 功能障碍有可能成为HF的有前途的治疗途径。 最近，我们和其他群体发现，对于控制细胞身份的基因很重要 独特的表观遗传学特征，例如，激活组蛋白修饰H3K4me3和Super-的广泛富集 增强子标记。这些发现促使我们的飞行员工作开发了第一个计算模型 发现新的EC大师监管机构。这种小说模型对两种表观遗传学进行了分析 景观以及基因表达网络。它成功地捕获了已知的EC认同基因 高灵敏度和准确性。该模型进一步揭示了许多排名最高的基因，没有报告的作用 在EC中，使他们承诺候选人成为新的EC认同基因。排名最高的基因之一是 转录因子4（TCF4），该因子在EC中显示细胞同一性基因的典型特征。 有趣的是，我们有初步数据，表明TCF4功能是维护EC的主调节器 身份。此外，与非输闭对照相比，HF患者心脏ECS的TCF4被下调。这 EC中TCF4的沉默导致EC分泌的蛋白TGFβ1的增加，刺激成纤维细胞 激活和肌纤维细胞转差，从而促进心脏纤维化。在此提案中，我们将 研究TCF4在EC身份维持中的作用。我们将进一步研究TCF4在 EC和成纤维细胞之间的串扰，并揭示TCF4作为预防HF心脏纤维化的治疗靶标。 该提案的成功完成将是第一个将TCF4定义为新型EC主管的人 维护EC表型和功能。我们将揭示一个被忽视的HF - EC身份丧失。 TCF4失调干扰了心脏内部的EC纤维细胞串扰，使HF中的心脏纤维化加剧。 EC特异性TCF4递送的治疗调节可能是治疗HF的新型方法。