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）：中性粒细胞的完美功能对于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持续几天生存细菌和真菌的持续攻击。在大量疾病中，嗜中性粒细胞对中性粒细胞的巨大选择压力使中性粒细胞成为迁移速度和达到远处靶标的能力方面最有效，最显着的细胞之一。但是，在几种情况下，中性粒细胞活性可能会产生比利益更多的损害。虽然嗜中性粒细胞激活在轻微创伤后是保护性的，但重大伤害后的超活跃中性粒细胞具有全身有害作用，即使在没有感染的情况下，也会有效损害几个器官和组织。许多疾病，例如慢性炎症性疾病，器官移植后的免疫反应或严重的哮喘形式，可能会因活性中性粒细胞加剧。其他时候，中性粒细胞也无反应，同时与免疫系统的下调，导致或促进化粪池状态。尽管在理解中性粒细胞内作用的信号分子和途径方面取得了巨大进步，但我们对疾病过程中嗜中性粒细胞变化的理解是有限的，因此，或因此，还是能够调节中性粒细胞在健康和疾病中的活性的能力，仅限于很少的选择。我们认为，低估嗜中性粒细胞活性的进步不仅可能来自分子生物学研究，而且还来自开发新工具，这些工具可以在与体内情况相关的条件下发现中性粒细胞行为。最近，我们证明了嗜中性粒细胞在小于细胞的微通道中移动时的惊人均匀运动能力。使用简单的通道网络，我们观察到中性粒细胞找到通往趋化剂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，以回答有关中性粒细胞在组织内部，健康和疾病，中性粒细胞生物学之间相互作用的机械和化学要求的问题，以及发现在烧伤和其他严重患者中控制炎症的新治疗策略。 公共卫生相关性：中性粒细胞的完美功能对于我们从近距离环境中的许多感染者的福祉和保护至关重要。 。但是，在几种情况下，中性粒细胞活性可能会产生比益处更大的损害，并且需要新的工具以更好地表征中性粒细胞在这些情况下。尽管目前研究中性粒细胞的方法仅针对细胞的化学刺激传递，但我们最近表明，小通道中嗜中性粒细胞的机械限制对于中性粒细胞行为至关重要。为了更好地了解烧伤损伤后活动的中性粒细胞改变，我们将应用新的微流体工具，并在健康和疾病状况下量化中性粒细胞对机械和化学刺激的组合的反应。这种理解可能会带来新的机会，以发现有效的治疗策略来控制烧伤和其他重症患者的炎症。