Neutrophil Decision Making in Confined Environments in Health and Disease

健康和疾病中受限环境中的中性粒细胞决策

• 批准号: 7859917
• 负责人: Daniel Irimia
• 金额: $ 30.09万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7859917
• 关键词: Asthma; Bacteria; Behavior; Biology; Burn injury; Cell Size; Cells; Chemical Stimulation; Chemicals; Chemotactic Factors; Chronic; Complex; Critical Illness; Decision Making; Development; Devices; Disease; Distant; Down-Regulation; Environment; Equilibrium; Extracellular Matrix; Goals; Healed; Health; Immigration; Immune System Diseases; Immune system; Infection; Infectious Agent; Inflammation; Inflammatory; Injury; Lead; Mechanics; Methods; Microfluidics; Minor; Modeling; Molecular Biology; Monitor; Morphology; Neutrophil Activation; Organ; Organ Transplantation; Pathway interactions; Patients; Personal Satisfaction; Process; Reaction; Signaling Molecule; Source; Speed; Stimulus; Therapeutic; Time; Tissues; Trauma; Variant; assault; base; behavior change; cell motility; chemokine; design; fungus; healing; heat injury; in vivo; inhibitor/antagonist; migration; neutrophil; novel therapeutics; pressure; public health relevance; response; septic; tool

DESCRIPTION (provided by applicant): Neutrophil perfect functioning is essential for our well-being. Without neutrophils, we could only survive a few days the constant assault of bacteria and fungi in our normal environment. A tremendous selective pressure on neutrophils to function perfectly in a large number of conditions made neutrophils one of the most efficient and remarkable cells in terms of migration speed and ability to reach distant targets. However, there are several conditions where neutrophil activity could produce more damage than benefits. While neutrophil activation is protective after minor trauma, hyper-active neutrophils after major injuries have systemic deleterious effects and can effectively damage several organs and tissues, even in the absence of infection. Many conditions like chronic inflammatory diseases, immune reactions post-organ transplantation, or severe forms of asthma can be exacerbated by active neutrophils. Other times, neutrophils become unresponsive, simultaneously with down-regulation of the immune system, leading to, or facilitating septic states. Despite tremendous advances in the understanding of signaling molecules and pathways acting inside neutrophils, our understanding of the changes in neutrophils during disease processes is limited, and consequently, or abilities to modulate the activity of neutrophils in health and disease, restricted to very few options. We believe that advances in understating of neutrophil activity could come not only from molecular biology studies, but also from the development of new tools that would enable the discovery of neutrophil behavior in conditions relevant to in vivo situations. Recently, we demonstrated the surprisingly uniform motility of neutrophils when moving in micro-channels smaller in size than the cell. Using simple networks of channels, we have observed the surprising ability of neutrophils to find the shortest path towards a source of chemoattractant. We will further develop these complex devices to answer questions about the mechanical and chemical requirements for neutrophil decision making inside tissues, in health and disease, regarding the interplay between these in neutrophil biology, and to uncover new therapeutic strategies for controlling inflammation in burn and other critically ill patients. PUBLIC HEALTH RELEVANCE: Neutrophil perfect functioning is essential for our well-being and protection against many infectious agents from our close environment. . However, there are several conditions where neutrophil activity could produce more damage than benefits and new tools are needed to better characterize neutrophils in these conditions. While current methods for studying neutrophils relay exclusively on chemical stimulation of the cells, we have recently shown that the mechanical confinement of the neutrophils in small channels is of utmost importance for neutrophil behavior. To better understand neutrophil alterations of activity following burn injuries, we will apply new microfluidic tools and quantify the responses of neutrophils to combined mechanical and chemical stimuli, in health and disease conditions. This understanding could results in new opportunities for uncovering effective therapeutic strategies for controlling inflammation in burn and other critically ill patients.

描述（由申请人提供）：中性粒细胞的完美功能对于我们的健康至关重要。如果没有中性粒细胞，我们只能在正常环境中的细菌和真菌的持续攻击下生存几天。中性粒细胞在多种条件下完美发挥作用所面临的巨大选择压力，使中性粒细胞成为迁移速度和到达远处目标能力方面最有效、最显着的细胞之一。然而，在某些情况下，中性粒细胞活动可能造成的损害大于益处。虽然中性粒细胞活化在轻微创伤后具有保护作用，但在重大损伤后过度活跃的中性粒细胞会产生全身性有害影响，即使在没有感染的情况下，也能有效损害多个器官和组织。活跃的中性粒细胞可能会加剧慢性炎症性疾病、器官移植后的免疫反应或严重的哮喘等许多病症。其他时候，中性粒细胞变得无反应，同时免疫系统下调，导致或促进败血症状态。尽管对中性粒细胞内部作用的信号分子和途径的理解取得了巨大进展，但我们对疾病过程中中性粒细胞变化的理解仍然有限，因此，在健康和疾病中调节中性粒细胞活性的能力仅限于很少的选择。我们相信，了解中性粒细胞活性的进展不仅来自于分子生物学研究，还来自于新工具的开发，这些工具能够发现与体内情况相关的条件下的中性粒细胞行为。最近，我们证明了中性粒细胞在尺寸小于细胞的微通道中移动时具有令人惊讶的均匀运动性。使用简单的通道网络，我们观察到中性粒细胞具有找到通向化学引诱剂来源的最短路径的惊人能力。我们将进一步开发这些复杂的设备，以回答有关健康和疾病中组织内中性粒细胞决策的机械和化学要求的问题，以及中性粒细胞生物学中这些因素之间相互作用的问题，并揭示控制烧伤和其他危重患者炎症的新治疗策略。 公共卫生相关性：中性粒细胞的完美功能对于我们的福祉和保护我们免受近距离环境中许多传染源的侵害至关重要。 。然而，在某些情况下，中性粒细胞活动可能产生的损害大于益处，因此需要新的工具来更好地表征这些情况下的中性粒细胞。虽然当前研究中性粒细胞的方法仅依赖于细胞的化学刺激，但我们最近表明，中性粒细胞在小通道中的机械限制对于中性粒细胞的行为至关重要。为了更好地了解烧伤后中性粒细胞活性的变化，我们将应用新的微流体工具并量化中性粒细胞在健康和疾病条件下对机械和化学刺激的反应。这种理解可能会为发现控制烧伤和其他危重患者炎症的有效治疗策略带来新的机会。