Mechanisms that Govern Vasculogenesis

控制血管发生的机制

• 批准号: 10462469
• 负责人: JAVIER SIERRA-PAGAN
• 金额: $ 3.99万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 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/10462469
• 关键词: 4-Hydroxy-Tamoxifen; ATAC-seq; 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; Complication; Conflict (Psychology); Data; Development; Disease; Embryo; Endothelial Cells; Enzymes; Exogenous Factors; F-Actin; Family suidae; Fibroblasts; Flow Cytometry; Gene Expression; Goals; Heart; Heart Diseases; Heart Injuries; Heart failure; Human; Immunohistochemistry; Impairment; In Vitro; Injections; Injury; Knockout Mice; Laboratories; Lead; Modeling; Morbidity - disease rate; Mus; Myocardial Infarction; Myocardial Ischemia; Myocardium; Natural regeneration; Patients; Perfusion; Phenocopy; Physicians; Physiological; Play; Process; Regenerative capacity; Retroviridae; Role; SMARCA4 gene; Scientist; Somatic Cell; 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; response to injury; transcription factor; translational model; vasculogenesis

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.

项目概要/摘要 缺血性心脏病（IHD）是世界上最主要的死亡原因，目前的治疗方法有限 无法促进受伤心脏的再肌肉化。在没有进行肌肉重建的情况下，受伤者 心肌梗塞 (MI) 后心脏会形成疤痕，并可能发展为心力衰竭。不足的 脉管系统和灌注受损是影响 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，需要开发新的治疗方法 疗法。一种方法是促进血管生成以增强心脏再生。临床试验 使用外源性因素治疗 IHD 已显示出相互矛盾的结果，这些结果归因于无法 这些因素驱动血管生成。因此，能够充分驱动血管生成的新疗法 IHD 的治疗是必要的。我们的实验室已证明 ets 变异因子 2 (ETV2) 是一种转录 对于血内皮 (HE) 谱系的发育来说是必要且充分的因素，因为 由于缺乏所有血液和脉管系统，ETV2 具有胚胎致死性。我们的最新证据 实验室表明 ETV2 是 HE 谱系的先驱转录因子。先锋转录 因子结合并松弛凝聚的染色质，以驱动基因表达所需的变化 细胞谱系的发育或规范。我们的初步数据显示 ETV2 与 BRG1，一种染色质重塑酶，已被证明可以与其他先驱转录协作 影响不同谱系发展的因素。然而，目前尚不清楚 ETV2-BRG1 相互作用如何发挥作用 与HE的发展和ETV2的先锋功能有关。此外，ETV2 的过度表达 显示可在体外将成纤维细胞重编程为功能性内皮细胞。不过，尚不清楚 ETV2 是否 过度表达可用于大型动物模型体内，以在 MI 后重新编程成纤维细胞，以增强 血管生成以治疗 IHD。因此，该提案的总体目标是开发治疗方法 通过了解控制血管生成的机制来制定 IHD 策略。我假设 ETV2 驱动 HE谱系以BRG1依赖性方式发育并且ETV2的体内过度表达将增强 通过促进血管生成来促进心脏再生。我将通过追求以下目标来检验这个假设：（1） 定义 BRG1 在 HE 谱系中 ETV2 先驱功能中的作用，以及 (2) 定义 in 的能力 使用猪模型进行心脏损伤后 ETV2 的体内重编程。完成这些研究将 增强我们对 ETV2 作为先锋因子如何靶向和放松凝集染色质的理解 BRG1 依赖性时尚驱动 HE 发育和血管生成。这些研究还将确定新的 可以增强重编程策略并可能导致新的开发的机制 心血管疾病的治疗。