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 组织功能也需要专门的实质细胞的协同功能 作为结构性(血管和间充质)细胞。先天免疫细胞，如巨噬细胞 它们在每个器官中都有分布和专长，现在是支持组织中公认的参与者 机能和长期健身。直到最近，中性粒细胞，一种最丰富的先天免疫 白细胞，已经占据了中心舞台，它们的功能多样性在 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线索，而那些形成网络的线索是 自身抗原和慢性炎症。与它们对疾病的贡献不同，我们有 开创性的研究表明，像巨噬细胞一样，中性粒细胞是正常组织的一部分。 动态平衡，它们可以适应健康有机体的多种环境。 这些新的发现促使人们需要更好地了解中性粒细胞是如何适应 以充分掌握它们对动态平衡的贡献，并确定 他们被不同类型的疾病拉拢的程度。这一点特别相关 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 器官受损可能会损害组织的适合性，增加疾病的易感性。这个 这项建议的首要目标是了解形成中性粒细胞的机制。 组织中的命运是确定它们对生物生理学的实际贡献的第一步 超越了免疫防御。从长远来看，我们希望利用这些知识建立 基于这些细胞的显著可塑性的精确医学。 为了实现这些目标，我们首先将重点放在肺作为模型器官来定义如何 中性粒细胞利用老鼠的遗传学自然获得血管生成特性，而 在组织修复中破坏这一程序的后果(目标1)。然后我们将询问如何 中性粒细胞在屏障组织中获得了令人惊讶的产生基质的特征，并使用 生物力学和成像工具，以确定该计划对屏障完整性的贡献 和皮肤修复(目标2)。