Neutrophil Migration in Three Dimensions

中性粒细胞的三维迁移

基本信息

批准号：
8500188
负责人：
Jonathan S Reichner
金额：
$ 18.15万
依托单位：
RHODE ISLAND HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8500188
关键词：
3-Dimensional Accounting Adhesions Adhesives Affect Anti-Inflammatory Agents Asthma Biochemical Biological Biological Assay Biology Blood Brain Cardiac Myocytes Cell Count Cell Surface Receptors Cell physiology Cells Chemotactic Factors Chemotaxis Chronic Granulomatous Disease Collaborations Collagen Complex Coupled Cues Data Detection Dimensions Disease Elastic Tissue Elasticity Elements Endothelial Cells Engineering Environment Event Exhibits Extracellular Matrix Extracellular Matrix Proteins Fibrin Fibroblasts Fibronectins Functional disorder Gel Gene Expression Generations Glass Goals Homeostasis Host Defense Human Immigration Impairment In Vitro Infection Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Injury Integrins Ion Channel Laboratories Lead Leukocyte Adhesion Deficiency Leukocytes Life Ligands Liquid substance Location Maps Mechanics Mediating Microscope Modeling Morphology Movement Muscle Nature Organ Paper Pathology Patients Performance at work Physiological Plastics Predisposition Production Property Publications Recurrence Relative (related person)Reperfusion Injury Reporting Research Research Design Research Personnel Rheumatoid Arthritis Series Signal Pathway Signal Transduction Site Skin Slide Source Stretching Structure Surface System Testing Therapeutic Therapeutic Intervention Time Tissues Traction Universities Variant Vascular Smooth Muscle Vasculitis Work Wound Healing base cell behavior cell motility density design improved in vivo information gathering injured insight kidney epithelial cell migration neutrophil novel therapeutics pathogen peripheral blood polyacrylamide gels prevent receptor research study respiratory distress syndrome response shear stress therapeutic effectiveness two-dimensional

项目摘要

DESCRIPTION (provided by applicant): Neutrophils are essential to innate host defense such that a decrease in the number of these cells in the peripheral blood presents heightened susceptibility to life threatening infections. In addition to being produced in adequate number, host defense also depends on the ability of neutrophils to function effectively. Patients with Leukocyte Adhesion Deficiency have normal numbers of neutrophils but they are genetically deficient in expression of integrins. Neutrophils in patients with Chronic Granulomatous Disease fail to produce adequate levels of microbiocidal oxidative species. In both cases, these functional deficits predispose patients to infections with opportunistic pathogens, recurrent infectious episodes and impairment of wound healing. Alternatively, an excessive neutrophil response can result in disease states characterized by collateral tissue damage such as respiratory distress syndrome, asthma, inflammatory bowel disease, ischemia/reperfusion injury, vasculitis and rheumatoid arthritis. Therefore, neutrophils must execute a sufficient but finely regulated response to infection or injury to promote a return to homeostasis. Neutrophils infiltrate any compromised tissue in the body in order to initiate an inflammatory response regardless of the fact that different bodily tissues offer substantial variations in composition an structure. Like all cells, neutrophils express a set of specific cell surface receptors that elicita functional response to biological elements within a microenvironment. It is clear that the physical nature of a microenvironment, such as its relative stiffness, is also an important regulator of function. The mechanisms that neutrophils use to respond to physical cues are not as clear as they are for receptor-ligand induced responses. Prior work from our laboratory hypothesized that soft, elastic tissues such as brain, may affect neutrophil function differently than stiffer tissues such as skin or muscle. Indeed, neutrophil adhesion, production of traction forces and migration were significantly different on fibronectin-coated matricies that varied only in stiffnes. The stiffnesses were all within the physiological range of tissue stiffnesses found in the body. Although this model provided a more relevant physiologic substrate than rigid materials such as plastic and glass, it is limited in that inflammatory neutrophils function within a 3-dimensional tissue environment. This is a proposal to engineer a tunable 3D in vitro system that will permit neutrophils to be studied under conditions that more closely model a tissue microenvironment. Moreover, the novelty of our system lies in that a given cell can be tracked in 2-dimensions and then in 3-dimensions thereby isolating dimension as a single experimental variable. Experiments will also determine whether integrins mediate the generation of traction forces and control migration of neutrophils in 3D as compared to 2D systems. A 3D in vitro system that accounts for the salient mechanical features of organs and tissues will provide a better means to predict effectiveness of therapeutics indicated for control of inflammation.

描述（由申请人提供）：中性粒细胞对于宿主先天防御至关重要，因此外周血中这些细胞数量的减少会增加对危及生命的感染的易感性。除了产生足够数量外，宿主防御还取决于中性粒细胞有效发挥作用的能力。白细胞粘附缺陷患者的中性粒细胞数量正常，但他们在整合素表达方面存在遗传缺陷。慢性肉芽肿病患者的中性粒细胞不能产生足够水平的杀菌氧化物质。在这两种情况下，这些功能缺陷使患者容易受到机会性病原体感染、反复感染发作和伤口愈合受损。或者，过度的中性粒细胞反应可导致以附带组织损伤为特征的疾病状态，例如呼吸窘迫综合征、哮喘、炎症性肠病、缺血/再灌注损伤、血管炎和类风湿性关节炎。因此，中性粒细胞必须对感染或损伤执行充分但精细调节的反应，以促进体内平衡的恢复。中性粒细胞会渗透到体内任何受损的组织，以引发炎症反应，尽管不同的身体组织在组成和结构上存在很大差异。与所有细胞一样，中性粒细胞表达一组特定的细胞表面受体，可引发对微环境内生物元素的功能反应。很明显，物理微环境的性质，例如其相对刚度，也是功能的重要调节因素。中性粒细胞对物理信号做出反应的机制并不像受体-配体诱导的反应那样清楚。我们实验室之前的工作假设，大脑等柔软、有弹性的组织对中性粒细胞功能的影响可能与皮肤或肌肉等较硬的组织不同。事实上，中性粒细胞的粘附、牵引力的产生和迁移在纤连蛋白包被的基质上显着不同，仅在硬度上有所不同。硬度均在体内组织硬度的生理范围内。尽管该模型提供了比塑料和玻璃等刚性材料更相关的生理基质，但其局限性在于炎症中性粒细胞在 3 维组织环境中发挥作用。这是一项设计可调 3D 体外系统的提案，该系统将允许在更接近地模拟组织微环境的条件下研究中性粒细胞。此外，我们系统的新颖之处在于可以在 2 维和 3 维中跟踪给定的细胞，从而将维度隔离为单个实验变量。实验还将确定与 2D 系统相比，整合素是否介导牵引力的产生并控制 3D 中中性粒细胞的迁移。考虑器官和组织显着机械特征的 3D 体外系统将提供更好的方法来预测控制炎症的治疗效果。