Fate-mapping of Cardiac Monocyte Recruitment and Specification

心脏单核细胞募集和规格的命运图谱

基本信息

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
项目类别：
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

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

展开

项目摘要

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代表了全球死亡的主要原因之一。尽管目前可用的治疗方法，心肌梗塞仍然是一个主要的指数事件，可能导致心力衰竭的进展。当前疗法的重点是防止进步重塑的进展包括发展纤维化。但是，在开发治疗方面几乎没有取得进展防止或逆转此重塑。近年来，已经证明心脏损伤引起了巨大的免疫响应涉及大多数已知的免疫细胞类型。近年来，还证明了单核细胞导致具有不同表达曲线的巨噬细胞种群中令人难以置信的多样性。实验在数量的小鼠和人类中，心血管疾病都证明了这种多样性。在此提案中， PI旨在调查这些潜水巨噬细胞种群如何以及何时获得其命运和研究干扰素信号作为该多样化的调节剂的潜力。该奖项的科学目标是确定巨噬细胞招募和心脏损伤后的规格。在此奖励期结束时，PI旨在确定何时单核细胞进入心脏会获得其特定的巨噬细胞转录曲线，如观察到的高度多样事先实验。 PI将利用新技术，包括插入式2光子成像和高级计算生物学技术。 PI还将确定干扰素信号在规范中的作用心脏损伤后的巨噬细胞种群以及修复和注射。这将由调节募集单核细胞中的干扰素信号传导。在此奖励期结束时，PI将产生更好地了解复杂的对心脏损伤的免疫反应是如何发生的。该建议的职业发展目标是帮助PI成功成为独立研究者。 PI先前已经获得了发育生物学博士学位，并完成了3年心脏免疫学的博士后培训。根据该奖项拟议的2年指导研究时间将为PI提供免疫学，计算生物学和赠款写作方面的正式培训。另外， Menorship团队和咨询委员会将提供有关技术技能，管理技能的培训和建议并做出早期职业决定。通过完成此奖励期，PI将获得必要的技能成为一名成功的独立研究人员。