Kindlin-3 signaling in neutrophils

中性粒细胞中的 Kindlin-3 信号传导

• 批准号: 10576419
• 负责人: Yan-Qing Ma
• 金额: $ 45.78万
• 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/10576419
• 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; Lysine; Mediating; Methods; Mus; Neutrophil Activation; Neutrophil Infiltration; Pathologic; Play; Predisposition; Process; Production; Property; Reactive Oxygen Species; Regulation; Research Project Grants; Resistance; Role; Signal Transduction; Site; Sterility; Stimulus; Testing; Tissues; Ubiquitin; Ubiquitination; Yeasts; experimental study; extracellular; inflammatory modulation; 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.

项目总结/文摘