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: 10659052
• 负责人: Derick Okwan-Duodu
• 金额: $ 42.63万
• 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/10659052
• 关键词: Abdomen; Abdominal Pain; Alzheimer' s Disease; Atlases; Award; Biopsy; Blood; Blood Cells; Blood Circulation; Brain; Brain imaging; Catalogs; Cells; Cessation of life; Chronic; Chronic Obstructive Pulmonary Disease; Circulation; Clinical; Code; Coronary Arteriosclerosis; Coupled; Cytometry; Detection; Diagnosis; Diagnostic; Digestion; Disease; Disease model; Early Diagnosis; Early Intervention; Epitopes; Etiology; Eye; Fibrosis; Foundations; Functional disorder; Gene Expression Profile; Genetic Screening; Genetic Transcription; Goals; Half-Life; Health; Heart; Homeostasis; Human; Image; Immune; Immune response; Individual; Infiltration; Kidney; Laboratories; Link; Liver; Lung; Mediating; Memory; Modality; Modern Medicine; Morbidity - disease rate; Nephritis; Nephrosis; Nephrotic Syndrome; Neutrophil Infiltration; Organ; Pancreas; Pathologic; Penetrance; Preventive measure; Proteins; Pulmonary Fibrosis; Pulmonary function tests; Reporter; Respiratory Failure; Sampling; Scanning; Sentinel; Signs and Symptoms; Solid; Stroke; Symptoms; System; Testing; Therapeutic Intervention; Time; Tissues; United States; antimicrobial; cell injury; dimensional analysis; early screening; flexibility; functional status; genetic testing; genomic aberrations; high dimensionality; human disease; improved; innovation; insight; mortality; neutrophil; novel; residence; screening; single-cell RNA sequencing; transcriptomics

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.

循环中性粒细胞高维图谱作为固体器官功能状态的报告 慢性实体器官疾病(CSOD)合计占美国死亡人数的大部分 各州。现代医学的一个中心目标是提高我们预测和检测CSOD的能力，以便 及早启动成功的治疗干预措施或安装适当的早期预防措施。几个 已经设计了一些方法来促进疾病的早期检测，包括基因测试和筛查 成像和实验室测试等模式。然而，相当多的民间社会组织保持沉默， 躲避即使是最警惕的临床眼睛，只有在为时已晚才能扭转病理生理时才出现 这种疾病的危害。识别非侵入性、可访问、敏感和全面的记者系统 同时评估许多固体器官的状况将扩大 显性疾病发生前的治疗干预。 细胞损伤和损害是所有器官疾病的先兆，它会触发一种免疫反应， 可能被转录编码成监视免疫细胞。血液循环通达各实心器官 因此提供了一个很好的进入器官状态的入口。具体地说，中性粒细胞，最丰富的 在人体内，免疫细胞几乎渗透到所有处于动态平衡状态的器官。与他们的名声相反 中性粒细胞是非特异性的抗微生物战斗细胞，已经进化为异质的、功能多样的细胞。 参与器官动态平衡和调节CSOD。高维方法的出现，如 正如单细胞飞行时间(CyTOF)和单细胞RNA测序(scRNA-seq)所揭示的 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， 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的是， 中性粒细胞不会在它们寄居的组织中建立永久居留。此功能与 中性粒细胞的半衰期很短，但转录延展性很强，这使它们成为很好的服务对象 作为机关身份的哨兵和记者。简而言之，渗入器官的中性粒细胞有可能返回 通过重要的器官特异性代码进入体循环，这些代码可以预测体内平衡状态 心烦意乱的病态。这项提议将利用中性粒细胞的这些特征来创造一种 他们的转录特征的全面图谱，这样任何组织特异性的失调都将是 被检测为这些转录签名的变化。如果成功，我们设想一个临床世界，在那里 对中性粒细胞转录特征的血液分析将在症状出现之前很早就发现潜伏性疾病， 促使及早干预。