Microfluidic tools for probing neutrophil reversed migration

用于探测中性粒细胞反向迁移的微流体工具

• 批准号: 9096701
• 负责人: Daniel Irimia
• 金额: $ 26.1万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-24 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9096701
• 关键词: Address; Adopted; Alzheimer' s Disease; Animal Model; Animal Organ; Atherosclerosis; Blood; Blood Circulation; Blood specimen; Body Surface; C-reactive protein; Cells; Chemicals; Chronic; Device Designs; Devices; Diabetes Mellitus; Diagnosis; Diagnostic; Disease; Early Diagnosis; Early Intervention; Early treatment; Flow Cytometry; Gene Proteins; Genomics; Genotype; Goals; Health; Heart Diseases; Histology; Human; Imaging Techniques; Immune; In Vitro; Infection; Inflammation; Inflammation Process; Injury; Knowledge; Lead; Leukocytes; Life Style; Liver; Lung diseases; Malignant Neoplasms; Mechanics; Metabolic Diseases; Methods; Microbe; Microfluidic Microchips; Microfluidics; Molecular Profiling; Monitor; Morbidity - disease rate; Mus; Nephritis; Organ; Pathology; Patients; Pattern; Peptide Hydrolases; Pharmaceutical Preparations; Phenotype; Population; Process; Proteomics; Protocols documentation; Reactive Oxygen Species; Renal clearance function; Research; Risk; Role; Series; Staging; Sterility; Stroke; Techniques; Technology; Testing; Time; Tissues; Tracer; Transgenic Animals; Work; Zebrafish; aging population; biomarker discovery; cardiovascular risk factor; design; differential expression; effectiveness measure; extracellular; human migration; improved; in vivo; in vivo imaging; inflammatory marker; macrophage; migration; mortality; neutrophil; novel; protein expression; research study; residence; tool; trafficking

DESCRIPTION (provided by applicant): Seven out of ten top leading causes of mortality in the developed world (from atherosclerosis and heart disease to diabetes and cancer) share a common pathology: chronic inflammation. Diagnosis is often made when the damage to critical organs is already significant and irreversible because none of the existing inflammation markers is appropriate for early detection of chronic inflammation conditions. To change the status-quo, we will rely on emerging knowledge proposing new roles for neutrophils - the typical innate immune cell to protect us against microbes - in chronic inflammation. Observations in transgenic animals showed that some neutrophils are capable of reversing migration from tissues to circulation after responding to a sterile injury. Recently, we have been able to replicate the reversed-migration patterns in a novel in vitro device. The major goal of this proposal is to continue improving the design of these devices, to identify and characterize the modulators of reversed-migration in vitro, and to design more sophisticated technologies that can separate the neutrophils undergoing reversed migration, for subsequent genomic and proteomic analysis. These tools would enable us to characterize the reversely-migrated neutrophils in detail and to identify specific markers that could differentiate the reversely-migrated neutrophils from naive neutrophils in blood samples from patients with chronic inflammation. If successful, our research could lead to new methods for monitoring chronic inflammation, could enable early diagnosis, allow sufficient time to adopt lifestyle changes, assist early treatments, and could have major implications for reducing morbidity and mortality associated with chronic inflammation diseases.

描述（由申请人提供）：在发达国家，十分之七的主要死亡原因（从动脉粥样硬化和心脏病到糖尿病和癌症）都有一个共同的病理：慢性炎症。由于现有的炎症标志物都不适合早期发现慢性炎症状况，因此通常在关键器官的损害已经明显且不可逆转时才进行诊断。为了改变现状，我们将依靠新兴的知识提出中性粒细胞的新作用-典型的先天免疫细胞，以保护我们免受微生物-在慢性炎症。对转基因动物的观察表明，在对无菌损伤作出反应后，一些中性粒细胞能够逆转从组织向循环的迁移。最近，我们已经能够在一种新的体外装置中复制反向迁移模式。本提案的主要目标是继续改进这些装置的设计，识别和表征体外反向迁移的调节剂，并设计更复杂的技术，可以分离正在进行反向迁移的中性粒细胞，用于随后的基因组和蛋白质组学分析。这些工具将使我们能够详细地表征反向迁移的中性粒细胞，并确定能够区分反向迁移的中性粒细胞与慢性炎症患者血液样本中初始中性粒细胞的特定标记。如果成功，我们的研究可能会带来监测慢性炎症的新方法，可以实现早期诊断，有足够的时间采取生活方式的改变，协助早期治疗，并可能对降低与慢性炎症疾病相关的发病率和死亡率产生重大影响。

项目成果

Neutrophils self-limit swarming to contain bacterial growth in vivo.

• DOI: 10.1126/science.abe7729
• 发表时间: 2021-06-18
• 期刊: Science (New York, N.Y.)
• 作者: Kienle K;Glaser KM;Eickhoff S;Mihlan M;Knöpper K;Reátegui E;Epple MW;Gunzer M;Baumeister R;Tarrant TK;Germain RN;Irimia D;Kastenmüller W;Lämmermann T
• 通讯作者: Lämmermann T