Cardiovascular regeneration and pioneer factors

心血管再生和先锋因素

• 批准号: 10649338
• 负责人: Daniel J. Garry
• 金额: $ 69.74万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-20 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649338
• 关键词: ATAC-seq; Adult; Affect; Algorithms; American; Applications Grants; Binding; Bioinformatics; Biological Assay; Biology; Biotechnology; Blood; Blood Vessels; Bypass; Cardiac; Cardiovascular Diseases; Cardiovascular system; Caring; Cellular biology; ChIP-seq; Chromatin; Chronic; Communication; Coronary Artery Bypass; DNA; Data; Development; Diabetes Mellitus; Disease; Dissection; Embryo; Embryonic Development; Endothelium; Engineering; Fibroblasts; Future; Gene Expression; Genes; Genetic; Genetic Engineering; Genetic Models; Genetic Transcription; Goals; Heart Injuries; Hematopoietic; In Vitro; Incidence; Inflammatory; Injury; Knockout Mice; Machine Learning; Maps; Mediating; Medical; Modeling; Morbidity - disease rate; Morphogenesis; Mus; Natural regeneration; Nature; Nucleosomes; Obesity; Pathway interactions; Patients; Peripheral arterial disease; Publications; Publishing; Regulator Genes; Research; Role; SMARCA4 gene; SMARCA5 gene; Societies; Specific qualifier value; TAL2 gene; Therapeutic; Therapeutic Intervention; Vascular Diseases; cardiac regeneration; cardiac repair; clinically significant; conditional knockout; in vivo; innovation; knock-down; limb amputation; mortality; mouse model; mutant; neovascularization; novel; novel therapeutics; progenitor; programs; recruit; response to injury; revascularization surgery; single-cell RNA sequencing; stem cells; transcription factor

Cardiovascular diseases are both common and deadly. For example, peripheral artery disease affects more than 10M Americans resulting in more than 150,000 limb amputations each year in the U.S. In addition, more than 300,000 patients have coronary artery bypass grafting (surgical revascularization). Current medical therapies for vascular disease include limb amputation and vascular bypass grafting--these therapeutic interventions have significant limitations. These diseases are chronic, debilitating, lethal and they warrant new and novel therapies. Previous studies have demonstrated the essential role for pioneer factors that modulate chromatin accessibility and thereby impact the binding of early transcriptional regulators for lineage specification. We have recently demonstrated that ETV2 is an essential pioneer factor for endothelial, vascular and blood lineages. We have used global and conditional gene disruption strategies, fate-mapping, gene editing, single cell RNA-seq, ATAC-seq and ChIP-seq assays to provide supportive data for this application. In addition, we defined an important ETV2-miR130a-PDGFRa cascade that governs endothelial development. Furthermore, our recent publications and our preliminary data support the overall hypothesis that ETV2 is a pioneer factor that regulates the specification of the endothelial lineage. In these proposed studies, we will use a number of unique genetic models that we have engineered and we take an innovative strategy to define the mechanisms whereby ETV2 functions as a pioneer factor to regulate cardiovascular regeneration. To examine our hypotheses, we will address the following specific aims: Specific Aim #1: Specific Aim #1: To further define the mechanisms whereby ETV2 functions as a pioneer factor during embryogenesis and reprogramming to the endothelial lineage; Specific Aim #2: To define the role of chromatin modifying factors and ETV2 during embryogenesis and reprogramming to the endothelial lineage and Specific Aim #3: To examine the factors that promote ETV2 mediated reprogramming of the endothelial lineage in vitro and in vivo. These aims will utilize our recently engineered genetic mouse models, ATAC-seq, MNase-seq, ChIP-seq, inducible mouse model, cardiac injury model in the adult mouse, novel and bioinformatics algorithms to comprehensively define the mechanisms whereby ETV2 functions as a pioneer factor and will serve as prelude for therapeutic initiatives to engineer and promote regeneration of the cardiovascular lineages. Given the tremendous morbidity and mortality of cardiovascular disease in our society, the potential impact of this proposal is significant.

心血管疾病既常见又致命。例如，外周动脉疾病影响更多 超过1000万美国人导致超过150，000截肢每年在美国此外，更多 超过30万名患者接受了冠状动脉旁路移植术（外科血管重建术）。当前医学 血管疾病的治疗方法包括截肢和血管旁路移植术，这些治疗方法 干预措施有很大的局限性。这些疾病是慢性的、使人衰弱的、致命的， 和新疗法。先前的研究已经证明了调节细胞凋亡的先驱因子的重要作用。 染色质可及性，从而影响谱系的早期转录调节因子的结合 规范.我们最近已经证明ETV 2是内皮、血管内皮细胞和血管内皮细胞的一个重要的先锋因子。 和血统我们已经使用了全局和条件基因中断策略，命运定位，基因 编辑、单细胞RNA-seq、ATAC-seq和ChIP-seq测定，以为该应用提供支持性数据。在 此外，我们定义了一个重要的ETV 2-miR 130 a-PDGFR α级联反应，其控制内皮发育。 此外，我们最近的出版物和我们的初步数据支持总体假设， ETV 2是调节内皮谱系特化的先驱因子。在这些建议中， 研究，我们将使用一些独特的基因模型，我们已经设计，我们采取了创新的 定义ETV 2作为调节心血管疾病的先驱因子的机制的策略 再生为了检验我们的假设，我们将讨论以下具体目标：具体目标#1： 具体目标#1：进一步定义ETV 2在治疗过程中作为先锋因子发挥作用的机制。 胚胎发生和重编程为内皮细胞谱系;具体目标#2：确定 胚胎发生过程中的染色质修饰因子和ETV 2以及重编程至内皮细胞 谱系和具体目标#3：检查促进ETV 2介导的细胞重编程的因子。 在体外和体内的内皮细胞谱系。这些目标将利用我们最近设计的基因小鼠 模型，ATAC-seq，MNase-seq，ChIP-seq，诱导型小鼠模型，成年小鼠心脏损伤模型， 新的和生物信息学算法，以全面定义ETV 2作为一个功能的机制， 先锋因素，并将作为治疗计划的前奏，以工程师和促进再生的 心血管谱系鉴于我国心血管疾病的发病率和死亡率极高， 社会，这一建议的潜在影响是巨大的。

项目成果

SeATAC: a tool for exploring the chromatin landscape and the role of pioneer factors.

• DOI: 10.1186/s13059-023-02954-5
• 发表时间: 2023-05-22
• 期刊: GENOME BIOLOGY
• 影响因子: 12.3
• 作者: Gong, Wuming;Dsouza, Nikita;Garry, Daniel J.
• 通讯作者: Garry, Daniel J.