Transient Obstruction of Capillary Networks by Chromatin Yarns from Neutrophils in Older Adults

老年人中性粒细胞染色质纱线对毛细血管网络的短暂阻塞

• 批准号: 8953369
• 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: 2015-08-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8953369
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Age; Biochemistry; Biological Assay; Biomechanics; Blood Circulation; Blood capillaries; Blood flow; Cells; Cessation of life; Chromatin; Chromatin Fiber; Clinical Medicine; Coagulation Process; Communities; Complex; Deoxyribonucleases; Disease; Diverticulitis; Elderly; Enzymes; Fibrin; Frequencies; Goals; Guide prevention; Health; Histones; Hypoxia; Immunity; In Vitro; Infection; Inflammation; Injury; Kidney; Lead; Length; Leukocytes; Link; Lung; Lupus; Measurement; Measures; Microfluidic Microchips; Microfluidics; Molecular; Necrosis; Neutrophil Activation; Normal tissue morphology; Obstruction; Organ; Outcome; Patients; Pneumonia; Populations at Risk; Pre-Eclampsia; Preventive Intervention; Risk Factors; Role; Technology; Testing; Time; Tissues; Translations; Travel; Vasculitis; Whole Blood; base; capillary; circulating DNA; design; extracellular; high reward; high risk; hydrodynamic flow; improved; in vivo; injury and repair; mortality; neutrophil; new technology; novel; older patient; public health relevance; renal ischemia; tool; venule

 DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is a common problem in clinical medicine and a key risk factor for AKI in older adults is community-acquired pneumonia. Of more than 1 million patients in the US who are hospitalized with community-acquired pneumonia every year, between 10 and 20% of develop AKI, and the associated mortality among these is as high as 10%. To better understand AKI after pneumonia, we will test the hypothesis that neutrophils, hyper-activated by the infection, die and release decondensed chromatin, leading to the formation of large chromatin yarns, and contributing to transient, local ischemia of the kidney tissue and subsequent AKI. The role of decondensed chromatin released from neutrophils in AKI has not yet been unexplored. Unlike previous studies of neutrophil-derived chromatin in the context of disease, which converged on the biochemistry of the chromatin-associated histones and enzymes, and the molecular mechanisms of neutrophil death and chromatin release, we will focus on the biomechanics of chromatin fibers and yarns formation, release, and trapping in conditions of flow. The major challenges for this project are technological. We will address this challenge by designing a unique set of microfluidic tools, which will enable us to probe the complex biomechanics of chromatin released by overly-activated neutrophils in vitro. If successful, our study will validate the formation of chromatin yarns as a critical mechanism for blood flow obstructions, which is distinct from the classical fibrin clots. The obstruction of blood flow in chromatin-yarns trapping in capillary networks could have significant implication for other diseases in which infections and inflammation result in secondary organ injury.

 描述（由适用提供）：急性肾脏损伤（AKI）是临床医学中的一个常见问题，而老年人AKI的关键危险因素是社区获得的肺炎。在美国有超过100万患者中，每年在社区获得的肺炎住院，占AKI的10％至20％的患者，其中相关的死亡率高达10％。为了更好地理解肺炎后的AKI，我们将检验以下假设：中性粒细胞因感染，死亡和释放反应的染色质而过度激活，导致形成大型染色质纱，并有助于肾脏组织的短暂性，局部缺血，并随后的AKI。在AKI中释放从中性粒细胞释放的染色质的染色质的作用尚不是出乎意料。与先前对疾病中嗜中性粒细胞衍生的染色质的研究不同，疾病的背景下，这种染色质融合了染色质相关组蛋白和酶的生物化学，以及中性粒细胞死亡和染色质质释放的分子机制，我们将专注于染色体纤维纤维和Yarns形成，释放和trapping和Flow conflops of Flow flow flow flow flow flow flow flow flow flow flow flow flow flow flow flow condects of flow flow的生物力学上的重点。该项目面临的主要挑战是技术。我们将通过设计一套独特的微流体工具来应对这一挑战，这将使我们能够在体外通过过度激活的中性粒细胞释放的染色质的复杂生物力学。如果成功，我们的研究将验证染色质纱的形成是血流目标的关键机制，这与经典的纤维蛋白切片不同。毛细血管网络中染色质蛋白质中血流的阻塞可能 对感染和感染导致继发器官损伤的其他疾病具有重要意义。