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(申请人提供)：急性肾损伤(AKI)是临床医学中常见的问题，老年人AKI的一个关键危险因素是社区获得性肺炎。在美国，每年有100多万因社区获得性肺炎住院的患者中，有10%到20%的人发生AKI，而这些人的相关死亡率高达10%。为了更好地了解肺炎后的AKI，我们将检验一种假设，即感染后过度激活的中性粒细胞死亡并释放去凝集的染色质，导致形成大的染色质纱线，并有助于肾脏组织的短暂局部缺血和随后的AKI。中性粒细胞释放的去凝集染色质在AKI中的作用尚未被发现。不同于以往中性粒细胞来源的染色质在疾病背景下的研究，集中在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释放的分子机制上，我们将重点关注染色质纤维和纱线在流动条件下形成、释放和捕获的生物力学。这个项目的主要挑战是技术上的。我们将通过设计一套独特的微流控工具来应对这一挑战，这将使我们能够在体外探索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，我们的研究将证实染色质纱线的形成是血流障碍的关键机制，这与经典的纤维蛋白凝块不同。染色质纱线在毛细血管网络中的血流受阻可能 对感染和炎症导致继发性器官损伤的其他疾病具有重要意义。