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 在美国，每年有超过 1000 万美国人因此而导致超过 150,000 例肢体截肢。此外， 超过 300,000 名患者接受了冠状动脉旁路移植术（血运重建手术）。目前医疗 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，需要新的治疗方法 和新疗法。先前的研究已经证明了调节先锋因素的重要作用 染色质可及性，从而影响谱系早期转录调节因子的结合 规格。我们最近证明 ETV2 是内皮、血管的重要先驱因子。 和血统。我们使用了全局和条件基因破坏策略、命运图谱、基因 编辑、单细胞 RNA-seq、ATAC-seq 和 ChIP-seq 分析为本应用提供支持数据。在 此外，我们定义了一个重要的 ETV2-miR130a-PDGFRa 级联，它控制内皮发育。 此外，我们最近的出版物和初步数据支持了总体假设： ETV2 是调节内皮谱系规范的先锋因子。在这些提议中 研究中，我们将使用我们设计的许多独特的遗传模型，并采取创新的方法 策略来定义 ETV2 作为调节心血管的先锋因子的机制 再生。为了检验我们的假设，我们将实现以下具体目标：具体目标#1： 具体目标#1：进一步定义 ETV2 在 胚胎发生和内皮细胞谱系重编程；具体目标#2：定义角色 胚胎发生和内皮细胞重编程过程中的染色质修饰因子和 ETV2 谱系和具体目标#3：检查促进 ETV2 介导的重编程的因素 体外和体内的内皮谱系。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、诱导小鼠模型、成年小鼠心脏损伤模型、 新颖的生物信息学算法来全面定义 ETV2 发挥作用的机制 先锋因素，并将作为治疗举措的前奏，以设计和促进再生 心血管谱系。鉴于我国心血管疾病的巨大发病率和死亡率 社会，该提案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.