High dimensional atlas of circulating neutrophils as reporters of solid organ functional status

循环中性粒细胞的高维图谱作为实体器官功能状态的报告者

• 批准号: 10554538
• 负责人: Derick Okwan-Duodu
• 金额: $ 38.87万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-21 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10554538
• 关键词: dimensional; atlas; circulating; neutrophils; reporters

High dimensional atlas of circulating neutrophils as reporters of solid organ functional status Chronic solid organ diseases (CSODs) collectively account for the majority of deaths in the United States. A central goal in modern medicine is to improve our ability to predict and detect CSODs in order to initiate successful therapeutic interventions early or to install appropriate early preventive measures. Several approaches have been devised to facilitate early detection of disease, including genetic testing and screening modalities such as imaging and laboratory tests. However, considerable number of CSODs lay silent and escape even the most watchful clinical eyes, only appearing when it is too late to reverse the pathophysiology of the disease. The identification of a non-invasive, accessible, sensitive, and comprehensive reporter system that simultaneously appraises the status of many solid organs would widen the window of opportunity for therapeutic intervention before overt disease occurs. Cellular injury and damage, which precede all organ-based disease, trigger an immune response that may be transcriptionally encoded into surveilling immune cells. The blood circulation accesses all solid organs and therefore provides an excellent portal into organ status. Specifically, neutrophils, the most abundant immune cells in humans, infiltrates nearly all organs under homeostasis. Contrary to their reputation as mere non-specific anti-microbial combatants, neutrophils have evolved as heterogeneous, functionally versatile cells that participate in organ homeostasis and mediate CSODs. The advent of high-dimensional approaches such as single-cell cytometry by time of flight (CyTOF) and single-cell RNA sequencing (scRNA-seq) have revealed numerous previously unknown neutrophil subpopulations with distinct transcriptional features. Moreover, tissue-infiltrating neutrophils assume specific organ-defined signatures. Unique from other immune cells, neutrophils do not establish permanent residence in the tissues they sojourn. This feature coupled with the neutrophils' short half-life yet significant transcriptional malleability renders them excellent candidates to serve as sentinels and reporters of organ status. In short, neutrophils that have infiltrated organs potentially return into the systemic circulation with vital organ-specific codes that may predict homeostatic state compared to perturbed, diseased states. This proposal will capitalize on these features of neutrophils to create a comprehensive atlas of their transcriptomics signatures, such that any tissue-specific dysregulation would be detected as an alteration in these transcriptional signatures. If successful, we envision a clinical world where blood analysis of neutrophil transcriptomic features would unveil lurking disease far before symptoms develop, prompting early intervention.

作为实体器官功能状态报告者的循环中性粒细胞的高维图谱 慢性实体器官疾病（CSODs）共同占美国死亡人数的大多数。 States.现代医学的中心目标是提高我们预测和检测CSOD的能力， 尽早采取成功的治疗干预措施或采取适当的早期预防措施。几 已经设计了一些方法来促进疾病的早期发现，包括基因检测和筛查 例如成像和实验室测试。然而，相当多的民间社会组织发展机构保持沉默， 即使是最警惕的临床眼睛，只有在为时已晚，无法扭转病理生理学时才出现 的疾病。一个非侵入性的，可访问的，敏感的，全面的报告系统的识别 同时评估许多实体器官的状况，将扩大机会之窗， 在明显的疾病发生之前进行治疗干预。 细胞损伤和损害先于所有器官疾病，引发免疫反应， 可以转录编码到监视免疫细胞中。血液循环进入所有实体器官 因此提供了一个进入器官状态的极好入口。特别是中性粒细胞， 人体内的免疫细胞，在体内平衡下几乎渗透到所有器官。与他们的名声相反， 作为非特异性的抗微生物战斗细胞，中性粒细胞已经进化为异质的、功能多样的细胞 参与器官内稳态并介导CSOD。高维方法的出现， 正如单细胞飞行时间流式细胞术（CyTOF）和单细胞RNA测序（scRNA-seq）所揭示的那样， 许多以前未知的中性粒细胞亚群具有不同的转录特征。此外，委员会认为， 组织浸润性中性粒细胞呈现特定器官定义的特征。与其他免疫细胞不同， 嗜中性粒细胞不能在它们寄居的组织中建立永久的居所。此功能与 中性粒细胞的短半衰期但显著的转录可塑性使它们成为很好的候选者 作为器官状况的哨兵和报告者。简而言之，浸润器官的中性粒细胞可能会返回 进入体循环与重要的器官特异性代码，可以预测稳态相比， 不安的病态状态这项提议将利用中性粒细胞的这些特征来创造一种新的免疫系统。 他们的转录组学签名的综合图谱，这样任何组织特异性失调将是 检测到这些转录特征的改变。如果成功，我们设想一个临床世界， 嗜中性粒细胞转录组特征的血液分析将在症状发展之前揭示潜伏的疾病， 促进早期干预。