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Non-canonical functions of neutrophils

中性粒细胞的非典型功能

基本信息

批准号：
10647764
负责人：
Andres Hidalgo
金额：
$ 56.4万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10647764
关键词：
Acute Applications Grants Autoantigens Automobile Driving Biology Biomechanics Blood Platelets Blood Vessels Bone Marrow Cancer Patient Cells Cessation of life Chromatin Chronic Circulation Containment Cues Data Disease Environment Exhibits Faculty Genetic Genetic Transcription Goals Grant Health Hematopoietic stem cells Homeostasis Human Imaging Device Immune Immunology Infection Infiltration Inflammation Inflammatory Innate Immune System Intestines Invaded Knowledge Laboratories Letters Leukocytes Light Lung Macrophage Malignant Neoplasms Malignant neoplasm of lung Mechanics Mediator Mesenchymal Modeling Molecular Mus Myeloid Cells Neutrophil Infiltration Normal tissue morphology Organ Organ Model Organism Pathogenicity Pathology Pattern Periodicity Phenotype Physiological Physiology Predisposition Process Property Proteome Role Shapes Signal Transduction Skin Source Stromal Cell-Derived Factor 1 Structure Testing Textbooks Tissues Trauma Vascular regeneration Work antimicrobial circadian cytotoxic defined contribution density fitness grasp insight interest lung injury migration mouse genetics neutrophil novel therapeutic intervention precision medicine preservation programs repaired skin wound tissue repair tool transcriptome

项目摘要

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特化的实质细胞的协调功能作为结构（血管和间充质）细胞。先天免疫细胞，如巨噬细胞在每一个器官中都有分布和专门化，现在被认为是支持组织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，已经占据了中心舞台，它们的功能多样性在人类免疫系统中被发现是重要的。疾病的背景。例如，癌症患者中的低密度嗜中性粒细胞是癌症的一个来源。血管生成和免疫抑制的线索，而那些形成NET是一个来源，自身抗原和慢性炎症。与它们对疾病的贡献相比，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它们可以适应健康生物体中的多种环境。这些新的发现提示需要更好地了解中性粒细胞如何适应不同的环境，以充分掌握他们的贡献，稳态，并确定在多大程度上它们被不同类型的疾病所吸收。这一点尤其重要在急性或慢性炎症的情况下，作为特定中性粒细胞命运的扰动可能会损害组织的适应性，并增加对疾病的易感性。的这项计划的首要目标是了解中性粒细胞的形成机制，作为确定它们对生物体生理学的实际贡献的第一步超越免疫防御从长远来看，我们希望利用这些知识来建立精确的医学是基于这些细胞的显著可塑性。为了实现这些目标，我们首先将重点放在肺作为模型器官，以定义如何中性粒细胞自然获得血管生成特性使用小鼠遗传学，在组织修复中破坏该程序的后果（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基质产生特征，生物力学和成像工具，以确定该计划对屏障完整性的贡献修复皮肤（目标2）。