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: 8258312
• 负责人: Daniel Irimia
• 金额: $ 29.79万
• 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/8258312
• 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; Patients; Personal Satisfaction; Process; Reaction; Signal Pathway; 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）：神经系统的完美运作对我们的福祉至关重要。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中存活几天。中性粒细胞在大量条件下完美发挥功能的巨大选择压力使中性粒细胞在迁移速度和到达远处目标的能力方面成为最有效和最显着的细胞之一。然而，有几种情况下，中性粒细胞活性可能产生更多的损害而不是益处。虽然中性粒细胞活化在轻微创伤后是保护性的，但在严重损伤后过度活化的中性粒细胞具有全身性有害作用，并且即使在没有感染的情况下也可以有效地损害几个器官和组织。许多疾病，如慢性炎症性疾病，器官移植后的免疫反应，或严重形式的哮喘，都可能因活性中性粒细胞而加重。其他时候，中性粒细胞变得无反应，同时下调免疫系统，导致或促进脓毒症状态。尽管在中性粒细胞内部作用的信号分子和途径的理解方面取得了巨大进展，但我们对疾病过程中中性粒细胞变化的理解是有限的，因此，或调节健康和疾病中中性粒细胞活性的能力，仅限于非常少的选择。我们相信，在低估中性粒细胞活性方面的进展不仅来自分子生物学研究，而且来自新工具的开发，这些新工具将能够在与体内情况相关的条件下发现中性粒细胞的行为。最近，我们证明了令人惊讶的均匀运动的中性粒细胞移动时，在尺寸小于细胞的微通道。使用简单的通道网络，我们观察到中性粒细胞找到通往化学引诱物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，以回答有关组织内中性粒细胞决策的机械和化学要求的问题，在健康和疾病中，关于中性粒细胞生物学中这些之间的相互作用，并发现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：神经系统的完美运作对于我们的健康和保护我们免受来自我们封闭环境的许多传染性病原体的侵害至关重要。.然而，有几种情况下，中性粒细胞活性可能产生更多的损害比好处和新的工具，需要更好地表征中性粒细胞在这些条件下。虽然目前研究中性粒细胞的方法完全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有效的治疗策略以控制烧伤和其他危重患者的炎症带来新的机会。