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Mechanisms that Govern Vasculogenesis

控制血管发生的机制

基本信息

批准号：
10687016
负责人：
JAVIER SIERRA-PAGAN
金额：
$ 0.54万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2020-09-28 至 2023-10-27
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10687016
关键词：
4-Hydroxy-Tamoxifen ATAC-seq Actins Adult Affect Anatomy Animal Model Animals Applications Grants Area Binding Blood Blood Vessels Cardiac Cardiac Death Cardiovascular Diseases Cardiovascular system Cause of Death Cell Lineage Cessation of life Characteristics Chromatin Chromatin Remodeling Factor Chronic Cicatrix Clinical Trials Clinical Trials Design Collaborations Complication Data Development Disease Embryo Endothelial Cells Enzymes Exogenous Factors Family suidae Fibroblasts Flow Cytometry Gene Expression Goals Heart Heart Diseases Heart Injuries Heart failure Human Immunohistochemistry Impairment In Vitro Infarction Injections Injury Knockout Mice Laboratories Modeling Morbidity - disease rate Mus Muscle Myocardial Infarction Myocardial Ischemia Myocardium Natural regeneration Patients Perfusion Phenocopy Physicians Physiological Process Proliferating Regenerative capacity Relaxation Retroviridae Role SMARCA4 gene Scientist Somatic Cell Specific qualifier value Techniques Testing Therapeutic Training Transgenic Organisms United States Variant Vascular Diseases cardiac regeneration cardiovascular disorder therapy chromatin remodeling clinically significant endothelial stem cell heart function improved in vivo interest ischemic injury mortality novel therapeutics overexpression porcine model postnatal period pre-clinical programs response to injury transcription factor translational model vasculogenesis

项目摘要

PROJECT SUMMARY/ABSTRACT Ischemic heart disease (IHD) is the leading cause of death in the world and current therapies are limited due to the inability to promote remuscularization of the injured heart. In the absence of remuscularization, the injured heart forms a scar following a myocardial infarction (MI) that can progress towards heart failure. Insufficient vasculature and impaired perfusion are critical factors affecting the morbidity and mortality observed in IHD. These cardiovascular diseases are chronic, debilitating, lethal and they warrant the development of novel therapies. One approach is to promote vasculogenesis in order to enhance heart regeneration. Clinical trials using exogenous factors to treat IHD have shown conflicting results that have been attributed to the inability of such factors to drive vasculogenesis. Therefore, new therapies that can fully drive vasculogenesis for the treatment of IHD are warranted. Our laboratory has shown that the ets variant factor 2 (ETV2) is a transcription factor that is both necessary and sufficient for the development of hematoendothelial (HE) lineages as loss of ETV2 is embryonically lethal due to the absence of all blood and vasculature. Recent evidence from our laboratory suggests that ETV2 functions as a pioneer transcription factor for the HE lineage. Pioneer transcription factors bind and relax condensed chromatin in order to drive gene expression changes necessary for the development or specification of cell lineages. Our preliminary data shows that ETV2 physically interacts with BRG1, a chromatin remodeling enzyme, which has been shown to collaborate with other pioneer transcription factors in the development of different lineages. However, it remains unclear how ETV2-BRG1 interactions might be related to HE development and the pioneer function of ETV2. Furthermore, overexpression of ETV2 has been shown to reprogram fibroblasts into functional endothelial cells in vitro. However, it is not known whether ETV2 overexpression can be used in vivo in a large animal model to reprogram fibroblasts after a MI to enhance vasculogenesis in order to treat IHD. Therefore, the overall goal of this proposal is to develop therapeutic strategies for IHD by understanding the mechanisms that govern vasculogenesis. I hypothesize that ETV2 drives HE lineage development in a BRG1 dependent fashion and that in vivo overexpression of ETV2 will enhance cardiac regeneration by promoting vasculogenesis. I will test this hypothesis by pursuing the following aims: (1) to define the role of BRG1 in the pioneer function of ETV2 in the HE lineage, and (2) to define the capacity of in vivo reprogramming by ETV2 following cardiac injury using a swine model. Completion of these studies will enhance our understanding of how ETV2, as a pioneer factor, targets and relaxes condensed chromatin in a BRG1-dependent fashion to drive HE development and vasculogenesis. These studies will also identify new mechanisms that can enhance reprogramming strategies and potentially lead to the development of new therapies for cardiovascular disease.

项目摘要/摘要缺血性心脏病(IHD)是世界上主要的死亡原因，目前的治疗方法由于无法促进受伤心脏的肌肉化。在没有肌肉化的情况下，受伤的人心肌梗死(MI)后，心脏会形成疤痕，可能会发展为心力衰竭。不足血管系统和血流灌注受损是影响IHD发病率和死亡率的关键因素。这些心血管疾病是慢性的、使人衰弱的、致命的，它们需要开发新的治疗。一种方法是促进血管生成，以促进心脏再生。临床试验使用外源性因素治疗IHD显示出相互矛盾的结果，这些结果被归因于无法这些因素推动了血管生成。因此，能够充分推动血管生成的新疗法 IHD的治疗是有必要的。我们的实验室已经证明ETS变体因子2(ETV2)是一种转录对血液内皮细胞(HE)谱系的发展既必要又充分的因素，如丧失由于缺乏所有的血液和血管，ETV2在胚胎上是致命的。最近的证据来自我们的实验室表明，ETV2是HE血统的先驱转录因子。先锋转录因子结合和松弛浓缩的染色质，以驱动必要的基因表达变化细胞谱系的发展或规范。我们的初步数据显示，ETV2在物理上与 BRG1，一种染色质重塑酶，已被证明与其他先驱转录协同作用不同血统发展的因素。然而，目前尚不清楚ETV2-BRG1相互作用如何与HE的发展和ETV2的先锋功能有关。此外，ETV2的过度表达已经被显示在体外可以将成纤维细胞重新编程为具有功能的内皮细胞。然而，目前尚不清楚ETV2是否在大型动物模型中可以使用过表达来重新编程心肌梗死后的成纤维细胞以增强血管生成以治疗IHD。因此，这项提案的总体目标是开发治疗通过了解控制血管生成的机制来制定IHD的策略。我假设ETV2驱动 BRG1依赖的谱系发育和ETV2在体内的过表达将增强通过促进血管生成来实现心脏再生。我将通过追求以下目标来检验这一假设：(1) 确定BRG1在ETV2在HE谱系中的先锋功能中的作用，以及(2)确定在使用猪模型心脏损伤后ETV2的活体重编程。完成这些研究后，加深我们对ETV2作为先驱因子如何靶向和松弛凝聚的染色质的理解依赖BRG1的方式来驱动HE的发育和血管生成。这些研究还将确定新的能够加强重新编程战略并可能导致开发新的心血管疾病的治疗方法。