Kindlin-3 signaling in neutrophils

中性粒细胞中的 Kindlin-3 信号传导

• 批准号: 10343425
• 负责人: Yan-Qing Ma
• 金额: $ 43.74万
• 依托单位: VERSITI WISCONSIN, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10343425
• 关键词: Acute Lung Injury; Anti-Inflammatory Agents; Arginine; Binding; Biology; COVID-19; Cells; Chemotaxis; Chronic; Co-Immunoprecipitations; Cytoplasmic Tail; Decision Trees; Disease; Endotoxemia; Event; Excision; Goals; HL-60 Cells; Hematopoietic; Human; Hydrolase; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Integrin Binding; Integrin beta Chains; Integrins; Lead; Lysine; Mediating; Methods; Mus; Neutrophil Activation; Neutrophil Infiltration; Pathologic; Play; Process; Production; Property; Reactive Oxygen Species; Regulation; Research Project Grants; Resistance; Role; Signal Transduction; Site; Sterility; Stimulus; Testing; Time; Tissues; Ubiquitin; Ubiquitination; Yeasts; base; experimental study; extracellular; insight; multicatalytic endopeptidase complex; mutant; neutrophil; novel; response; screening; ubiquitin-protein ligase; yeast two hybrid system

PROJECT SUMMARY/ABSTRACT Inflammation plays a pivotal role in the rapid removal of harmful stimuli, either sterile or infectious; however, uncontrolled inflammation can lead to a variety of chronic inflammatory disorders. Neutrophils constitute the front line of the innate immune response, and swiftly undergo a carefully choreographed process to locate and destroy potentially pathological threats. Neutrophil recruitment is an integrin-dependent, chemotaxis-directed process that is followed by production of reactive oxygen species (ROS) and release of neutrophil extracellular traps (NETs), together which serve to remove or kill the offending agents. To minimize collateral damage to host tissues, however, the killing functions of neutrophils must be carefully regulated in both a temporally and spatially controlled manner; the mechanisms at play to regulate neutrophil activation, however, remain poorly understood. Kindlin-3, an integrin β cytoplasmic domain binding partner, and an essential integrin activator in cells of hematopoietic origin, is known to play an important role in promoting integrin-mediated neutrophil recruitment to the sites of inflammation. Paradoxically, however, we have recently discovered that neutrophil kindlin-3 also acts to suppress ROS production and NET release in an integrin-binding independent manner. Thus, kindlin-3 in neutrophils possesses both pro- and anti-inflammatory properties, indicating that it may function as a bifunctional modulator of neutrophil activation. Interestingly, our preliminary studies have revealed that neutrophil kindlin-3 unexpectedly becomes degraded upon inflammatory challenges. Based on these findings, we propose that degradation of neutrophil kindlin-3 is a key step in the cellular decision tree regulating neutrophil activation under inflammatory conditions. The purpose of this application, therefore, is to explore novel, heretofore unexplored mechanisms regulating kindlin-3 degradation and to examine its functional significance in inflammatory responses. Two Specific Aims are proposed. In Specific Aim 1, we will determine the mechanism by which kindlin-3 undergoes degradation in stimulated neutrophils, including both human and mouse neutrophils. In Specific Aim 2, we will determine the functional significance of kindlin-3 degradation in neutrophils in response to inflammatory challenges, such as under pathological conditions of endotoxemia and acute lung injury. These timely and complementary studies will establish an important and novel role for kindlin-3 in neutrophils in modulating inflammatory responses. Findings made will fill important gaps in our understanding of neutrophil biology, and may lead to novel opportunities for developing more specific and safer anti-inflammatory strategies for treating complications in a whole host of inflammatory diseases, including the recently described inflammatory complications present in COVID-19.

项目摘要/摘要 炎症在无菌或感染性的有害刺激的快速去除中起关键作用。 不受控制的炎症会导致多种慢性炎症障碍。 先天免疫反应的前线，并挥动位置定位和 破坏潜在的病理威胁。 随后产生活性氧（ROS）和中性粒细胞extracellarr的过程 陷阱（网）一起去除或杀死犯罪者。 然而，宿主组织必须在时间和 空间控制的方式； 理解。 已知造血起源细胞在促进整联蛋白介导的中性粒细胞中起着重要作用 招募发病的部位，我们最近发现中性粒细胞 Kindlin-3还可以以独立的方式抑制ROS的产生和净净释放。 因此，嗜中性粒细胞中的Kindlin-3具有促和抗炎的特性，表明它可以 作为中性粒细胞激活的双功能调节剂的功能。 揭示了中性粒细胞Kindlin-3意外地在炎症的挑战上降解 这些发现，我们建议中性粒细胞的降解是阶级决策树的关键步骤 因此，调节炎性条件下的中性粒细胞激活。 探索小说，迄今未开发的机制，调节Kindlin-3降解并检查其 炎症反应中的功能意义。 确定Kindlin-3在刺激的中性粒细胞中降解的机制，包括 人和小鼠中性粒细胞。 响应炎症挑战的中性粒细胞中的降解，例如在病理条件下 内毒素血症和急性肺损伤。 Kindlin-3在中性粒细胞调节炎症反应中的新作用。 我们对中性粒细胞生物学的理解的差距 特定且更安全的抗炎策略，用于治疗整个遭到肿瘤的并发症 疾病，包括Covid-19中存在的炎症并发症。