Non-canonical functions of neutrophils

中性粒细胞的非典型功能

• 批准号: 10521656
• 负责人: Andres Hidalgo
• 金额: $ 56.06万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-16 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10521656
• 关键词: Acute; Applications Grants; Autoantigens; Automobile Driving; Biology; Biomechanics; Blood Circulation; Blood Platelets; Blood Vessels; Bone Marrow; CXCL12 gene; Cancer Patient; Cells; Cessation of life; Chromatin; Chronic; Containment; Cues; Data; Disease; Environment; Exhibits; Faculty; Genetic; Genetic Transcription; Goals; Grant; Health; Hematopoietic stem cells; Homeostasis; Human; Imaging Device; Immune; Immunology; Infection; Inflammation; Inflammatory; Innate Immune System; Intestines; Invaded; Knowledge; Laboratories; Letters; Leukocytes; Light; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Mechanics; Mediator of activation protein; Mesenchymal; Modeling; Molecular; Mus; Myeloid Cells; Neutrophilic Infiltrate; Normal tissue morphology; Organ; Organ Model; Organism; Pathogenicity; Pathology; Pattern; Periodicity; Phenotype; Physiological; Physiology; Predisposition; Process; Property; Proteome; Role; Shapes; Signal Transduction; Skin; Source; Structure; Testing; Textbooks; Time; Tissues; Trauma; Vascular regeneration; Work; antimicrobial; circadian; cytotoxic; defined contribution; density; fitness; grasp; insight; interest; lung injury; macrophage; migration; mouse genetics; neutrophil; novel therapeutic intervention; precision medicine; preservation; programs; repaired; skin wound; tissue repair; tool; transcriptome

Project Summary Tissue function demands the concerted function of specialized parenchymal cells, as well as structural (vascular and mesenchymal) cell. Innate immune cells, such as macrophages that populate and specialize in every organ, are now recognized actors in supporting tissue function and long-term fitness. Only recently, neutrophils, the most abundant innate immune leukocytes, have taken center stage and their functional diversity found important in the context of disease. For example, low density neutrophils in cancer patients are a source of angiogenic and immune-suppressive cues, whereas those that form NETs are a source of autoantigens and chronic inflammation. In contrast to their contributions to disease, we have pioneered studies showing that, like macrophages, neutrophils are part of normal tissue homeostasis and that they can adapt to multiple environments in the healthy organism. These new findings prompt the need to better understand how neutrophils adapt to the different environments to fully grasp their contributions to homeostasis, and to determine the extent to which they are co-opted by different types of disease. This is particularly relevant in the context of acute or chronic inflammation, as perturbations of specific neutrophil fates in organs may compromise tissue fitness, and increase the susceptibility to disease. The overarching goal of this proposal is to understand the mechanisms that shape neutrophil fates in tissues as a first step to define their actual contributions to organismal physiology beyond immune defense. In the long term, we ambition to use this knowledge to build precision medicine based on the remarkable plasticity of these cells. To achieve these goals, we will first focus on the lung as model organ to define how neutrophils naturally acquire angiogenic properties using mouse genetics, and the consequences of disrupting this program in tissue repair (Aim 1). We will then query how neutrophils acquire a surprising matrix-producing signature in barrier tissues, and use biomechanical and imaging tools to define the contribution of this program to barrier integrity and repair in the skin (Aim 2).

项目摘要 组织功能还需要专门的实质细胞的协同功能 作为结构（血管和间充质）细胞。先天免疫细胞，例如巨噬细胞 现在填充和专业的每个器官，现在是支持组织的公认的演员 功能和长期健身。直到最近，中性粒细胞，最丰富的先天免疫 白细胞已成为中心阶段，其功能多样性在 疾病的背景。例如，癌症患者的低密度中性粒细胞是 血管生成和免疫抑制提示，而形成网的人是 自身抗原和慢性炎症。与它们对疾病的贡献相反，我们有 开创性的研究表明，与巨噬细胞一样，中性粒细胞是正常组织的一部分 稳态，并且可以适应健康生物体的多种环境。 这些新发现促使需要更好地了解中性粒细胞如何适应 不同的环境以完全掌握其对体内平衡的贡献，并确定 它们由不同类型的疾病选择的程度。这特别重要 在急性或慢性炎症的背景下，作为特定中性粒细胞命运的扰动 在器官中可能会损害组织适应性，并增加对疾病的敏感性。这 该提案的总体目标是了解形成中性粒细胞的机制 组织中的命运是定义其实际贡献对有机生理的第一步 超越免疫防御。从长远来看，我们有野心使用这些知识来建立 精密医学基于这些细胞的显着可塑性。 为了实现这些目标，我们将首先专注于肺部作为模型器官，以定义 中性粒细胞自然使用小鼠遗传学获得血管生成特性，而 在组织修复中破坏该程序的后果（AIM 1）。然后我们会查询如何 中性粒细胞在屏障组织中获得令人惊讶的基质签名，并使用 生物力学和成像工具来定义该程序对障碍完整性的贡献 并在皮肤上修复（AIM 2）。