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（由申请人提供）：急性肾损伤（阿基）是临床医学中的常见问题，老年人阿基的关键风险因素是社区获得性肺炎。在美国每年因社区获得性肺炎住院的100多万患者中，10%至20%的患者发生阿基，相关死亡率高达10%。为了更好地了解肺炎后的阿基，我们将检验以下假设：感染后过度激活的中性粒细胞死亡并释放去致密的染色质，导致大染色质纱线的形成，并导致肾组织的短暂局部缺血和随后的阿基。中性粒细胞释放的去致密染色质在阿基中的作用尚未探索。与以前的研究嗜中性粒细胞衍生的染色质在疾病的背景下，集中在染色质相关的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，我们将专注于染色质纤维和纱线的形成，释放和捕获的流动条件下的生物力学。该项目的主要挑战是技术。我们将通过设计一套独特的微流体工具来解决这一挑战，这将使我们能够探测体外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线的形成是血流阻塞的关键机制，这与经典的纤维蛋白凝块不同。在毛细血管网中捕获的染色质纱线中的血流阻塞可能 对感染和炎症导致继发性器官损伤的其它疾病具有重要意义。