Regulation of neutrophil extracellular trap formation

中性粒细胞胞外陷阱形成的调节

• 批准号: RGPIN-2016-05726
• 负责人: McDonald, Patrick
• 金额: $ 2.26万
• 依托单位: Université de Sherbrooke
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=709650
• 关键词: Regulation; neutrophil; extracellular; trap; formation

Neutrophils are indispensable components of the innate immune system. A key functional response of these cells is their ability to release so-called neutrophil extracellular traps (NETs) a meshwork of extruded chromatin filaments that are decorated with histones, as well as with proteins originating from the cytoplasm or intracellular granules. NETs were first described a decade ago, as structures that entrap (whence the name) various microorganisms and can thus participate in their killing. NETs have since been detected in a variety of inflammatory contexts, and were shown to help in preventing the dissemination of microorganisms in animals models. As a result, it has become a widely held view that NETs must represent a major defense mechanism against infection. Despite this, the molecular mechanisms underlying NET formation, as well as the upstream signaling pathways, remain poorly understood. In the last decade, we published several studies documenting the signaling machinery of neutrophils and how it controls functional responses such as cytokine generation and delayed apoptosis. More recently, we began exploring how discrete signaling molecules also govern NETosis (i.e. NET generation) and in doing so, have observed that there are probably more steps involved in this process than previously appreciated. Objectives. The general goal of our research program is to shed light on the cellular processes and molecular mechanisms that control NETosis. In the first project (Aim 1), we will focus on cellular processes that affect chromatin extrusion and the formation of long DNA fibers. This will involve observing the entire NETosis phenomenon as it unfolds by live cell imaging, and identifying processes that only affect extrusion or filament formation. We will also determine whether filaments result from physical traction by moving cells; whether filament formation requires macromolecular guides or extracellular scaffolds; and whether chromatin might somehow be projected towards nearby cells. In the second project (Aim 2), we will investigate how discrete signaling components participate in controlling NETosis (and at which steps), as well as their inter-relationships; and whether NETosis can occur in the absence of reactive oxygen species production, which are deemed essential for this response. Feasibility. We have expertise in all of the experimental approaches that are required to carry out the proposed work. Significance. The proposed research program will substantially further our understanding of NETosis, a seemingly unique biological phenomenon, by identifying its discrete phases. These investigations will also shed light on various aspects of how NETosis is regulated, by identifying some of the underlying molecular mechanisms.

中性粒细胞是先天免疫系统不可缺少的组成部分。这些细胞的一个关键功能反应是它们释放所谓的中性粒细胞胞外陷阱（NETs）的能力，NETs是一种挤压染色质细丝的网络，由组蛋白装饰，以及来自细胞质或细胞内颗粒的蛋白质。net最早是在十年前被描述的，作为一种结构，它可以诱捕（因此得名）各种微生物，从而参与杀死它们。此后，NETs在各种炎症环境中被检测到，并被证明有助于防止动物模型中微生物的传播。因此，人们普遍认为net一定是一种主要的抗感染防御机制。