Fate-mapping of Cardiac Monocyte Recruitment and Specification

心脏单核细胞募集和规格的命运图谱

• 批准号: 10740228
• 负责人: Andrew Leighton Koenig
• 金额: $ 10.14万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740228
• 关键词: Address; Advisory Committees; Antigen-Antibody Complex; Award; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cause of Death; Cells; Computational Biology; Dendritic Cells; Development; Developmental Biology; Disease; Disease Progression; Doctor of Philosophy; Embryo; Ensure; Event; Fibrosis; Foundations; Gene Expression Profile; Genetic; Genetic Transcription; Goals; Grant; Heart; Heart Injuries; Heart failure; Hematopoietic stem cells; Homeostasis; Human; Hypertrophy; Image; Immune; Immune response; Immunology; Infarction; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Interferon Activation; Interferon Type I; Interferons; Knowledge; Left Ventricular Remodeling; Literature; Macrophage; Maps; Mentors; Mentorship; Minor; Morphology; Mus; Myocardial; Myocardial Infarction; Myocarditis; Myocardium; Persons; Phase; Play; Population; Population Dynamics; Principal Investigator; Reporter; Research; Research Personnel; Role; Signal Transduction; Specific qualifier value; Technical Expertise; Techniques; Technology; Testing; Time; Tissues; Training; United States; Writing; adverse outcome; beta-Chemokines; cardioprotection; career; career development; cell type; chemokine receptor; design; experimental study; gain of function; heart function; improved outcome; indexing; interferon alpha receptor; loss of function; monocyte; myocardial injury; new technology; post-doctoral training; prevent; recruit; repaired; single-cell RNA sequencing; skill acquisition; skills; spatiotemporal; success; therapeutic target; therapy development; tissue repair; tool; two-photon

Project Abstract Cardiovascular disease including myocardial infarction represents one of the leading causes of death worldwide. Despite currently available treatments, myocardial infarction remains a major index event which can lead to progression of heart failure. Current therapies focus on preventing the progression of adverse remodeling including development of fibrosis. However, little progress has been made in the development of treatments to prevent or reverse this remodeling. In recent years, it has been demonstrated that cardiac injury elicits an immense immune response involving the majority of known immune cell types. In recent years, it has also been demonstrated that the recruitment of monocytes leads to incredible diversity in macrophage populations with distinct expression profiles. Experiments in both mice and humans in numbers cardiovascular diseases has demonstrated this diversity. In this proposal, the PI aims to investigate how and when these diverse macrophage populations obtain their fate and investigate the potential of interferon signaling as a regulator of this diversification. The scientific goals of this award are to identify the spatiotemporal dynamics of macrophage recruitment and specification after cardiac injury. By the end of this award period, the PI aims to establish when monocytes entering the heart acquire their specific macrophage transcriptional profile as observed to be highly diverse in prior experiments. The PI will utilize new technologies including intravital 2-photon imaging and advanced computational biology techniques. The PI will also identify the role of interferon signaling in the specification of macrophage populations as well as in repair and inflammation after cardiac injury. This will be completed by modulating interferon signaling in recruited monocytes. At the end of this award period, the PI will have generated a better understanding of how the complex immune response to heart injury occurs. The career development goal of this proposal is to aid in the PI’s success in becoming an independent investigator. The PI has previously obtained a PhD in developmental biology and completed 3 years of postdoctoral training in cardiac immunology. The proposed 2-year mentored research time under this award will provide the PI with formal training in immunology, computational biology, and grant-writing. Additionally, the mentorship team and advisory committee will provide training and advice on technical skills, management skills, and making early career decisions. By completing this award period, the PI will have acquired the skills necessary to become a successful independent researcher.

项目摘要 包括心肌梗塞在内的心血管疾病是全世界死亡的主要原因之一。 尽管目前有可用的治疗方法，心肌梗塞仍然是一个主要的指标事件，可能导致 目前的治疗重点是预防不良重构的进展。 然而，在治疗方法的开发方面却进展甚微。 阻止或逆转这种重塑。 近年来，已经证明心脏损伤会引起巨大的免疫反应，涉及 近年来，还证明了大多数已知的免疫细胞类型的招募。 单核细胞导致巨噬细胞群体具有不同的表达谱实验令人难以置信的多样性。 在小鼠和人类中，心血管疾病的数量已经证明了这种多样性。 PI 旨在研究这些不同的巨噬细胞群体如何以及何时获得它们的命运和 研究干扰素信号作为这种多样化调节剂的潜力。 该奖项的科学目标是确定巨噬细胞招募的时空动态和 在此奖励期结束时，PI 的目标是确定单核细胞何时出现。 进入心脏获得其特定的巨噬细胞转录谱，正如观察到的那样，巨噬细胞转录谱在 PI 将利用包括活体 2 光子成像和先进技术在内的新技术。 PI 还将确定干扰素信号传导在规范中的作用。 巨噬细胞群以及心脏损伤后的修复和炎症将完成这一过程。 在此奖励期结束时，PI 将产生调节招募的单核细胞中的干扰素信号。 更好地了解对心脏损伤的复杂免疫反应是如何发生的。 该提案的职业发展目标是帮助 PI 成功成为一名独立的 该 PI 此前已获得发育生物学博士学位并完成了 3 年的研究。 该奖项拟议的 2 年研究导师时间将是心脏免疫学的博士后培训。 为 PI 提供免疫学、计算生物学和资助写作方面的正式培训。 导师团队和顾问委员会将提供技术技能、管理技能、 通过完成这个奖励期，PI 将获得必要的技能。 成为一名成功的独立研究员。