Fate-mapping of Cardiac Monocyte Recruitment and Specification

项目摘要 包括心肌梗塞在内的心血管疾病是世界范围内的主要死亡原因之一。 尽管目前有可用的治疗方法，心肌梗死仍然是一个重大的指标事件，可能导致 心力衰竭的进展。目前的治疗方法侧重于防止不良重塑的进展。 包括纤维化的发展。然而，在开发治疗方法方面进展甚微。 防止或逆转这种重塑。 近年来，已有研究表明，心脏损伤可引起巨大的免疫反应，涉及 大多数已知的免疫细胞类型。近年来，也有证据表明，招聘 单核细胞导致了具有不同表达谱的巨噬细胞群体令人难以置信的多样性。实验 无论是在老鼠身上还是在人类身上，心血管疾病都表现出了这种多样性。在这份提案中， PI旨在调查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的调节因素的潜力。 该奖项的科学目标是确定巨噬细胞募集的时空动力学和 心脏损伤后的规范。到这个获奖期结束时，PI的目标是建立单核细胞 进入心脏获得其特殊的巨噬细胞转录图谱，观察到在 先前的实验。PI将利用新技术，包括体内双光子成像和先进的 计算生物学技术。PI还将确定干扰素信号在规范 巨噬细胞群以及心脏损伤后的修复和炎症。这项工作将于 调节招募的单核细胞中的干扰素信号。在此授权期结束时，PI将生成 更好地了解心脏损伤的复杂免疫反应是如何发生的。 这项建议的职业发展目标是帮助PI成功地成为一名独立的 调查员。该协会此前已获得发育生物学博士学位，并完成了3年的 心脏免疫学博士后培训。根据该奖项，建议的两年指导研究时间将 为PI提供免疫学、计算生物学和赠款撰写方面的正式培训。此外， 指导小组和咨询委员会将提供关于技术技能、管理技能、 以及在职业生涯早期做出决定。通过完成这一授权期，PI将获得必要的技能 成为一名成功的独立研究人员。

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.