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.