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，周围动脉疾病影响更多 除1000万美国人每年在美国产生超过150,000个肢体截肢，此外， 超过300,000名患者有冠状动脉搭桥术（手术血运重建）。当前的医疗 血管疾病的疗法包括肢体截肢和血管搭桥术 - 这些治疗 干预措施有重大局限性。这些疾病是长期的，令人衰弱的，致命的，它们保证了新的 和新颖的疗法。先前的研究表明了调节的先锋因素的重要作用 染色质的可及性，从而影响早期转录调节剂的结合以进行谱系 规格。我们最近证明，ETV2是内皮，血管的重要先锋因素 和血统。我们已经使用了全球和有条件的基因破坏策略，命运映射，基因 编辑，单细胞RNA-SEQ，ATAC-SEQ和CHIP-SEQ分析，为此应用提供支持数据。在 此外，我们定义了一个重要的ETV2-MIR130A-PDGFRA级联反应，该级联控制着内皮发育。 此外，我们最近的出版物和我们的初步数据支持了以下总体假设 ETV2是调节内皮谱系规范的先驱因素。在这些提议中 研究，我们将使用许多我们已经设计的独特遗传模型，并进行创新 定义ETV2作为调节心血管的先驱因素的机制的策略 再生。为了审查我们的假设，我们将解决以下特定目的：特定目的＃1： 特定目的＃1：进一步定义ETV2在此过程中起先锋因素的机制 胚胎发生和重编程到内皮谱系；特定目的＃2：定义 在胚胎发生和重新编程中，染色质修饰因子和ETV2对内皮 谱系和特定目的＃3：检查促进ETV2介导的重新编程的因素 体外和体内内皮谱系。这些目标将利用我们最近设计的遗传鼠标 模型，Atac-Seq，Mnase-Seq，Chip-Seq，诱导小鼠模型，成年小鼠中心脏损伤模型， 新颖和生物信息学算法全面定义了ETV2作为一种机制 先驱因素，并将作为治疗计划的前奏，以设计和促进 心血管谱系。考虑到我们的心血管疾病的巨大发病率和死亡率 社会，该提议的潜在影响很大。

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.