Neutrophil Extracellular Traps and Host Immunity

中性粒细胞胞外陷阱和宿主免疫

基本信息

批准号：
10228919
负责人：
Jyotika Sharma
金额：
$ 40.5万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-04 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10228919
关键词：
Acute Airway Disease Anti-Bacterial Agents Antiinflammatory Effect Antineoplastic Agents Autoimmune Diseases Autophagocytosis Bacterial Infections Binding Proteins Blood specimen Breast Cancer Treatment Bypass Chromatin Chromatin Fibril Chronic Chronic Granulomatous Disease Clinical Trials Colitis Colon Communicable Diseases Complex Cysteine Data Defect Disease Estrogen Receptors Exhibits FDA approved Functional disorder Future Generations Genetic Transcription Histones Human Immune response Immunity Impairment In Vitro Infection Inflammation Inflammatory Lamin B1 Life Link Lung Lung infections Measures Mediating Modeling Molecular Mus Mutation NADPH Oxidase Neutrophil Activation Nuclear Lamina Pathology Pathway interactions Patients Peptide Hydrolases Phagocytes Phagocytosis Pharmaceutical Preparations Preclinical Testing Predisposition Proteins Publications Publishing Reactive Oxygen Species Reporting Research Respiratory Burst Role Seminal Signal Pathway Sodium Dextran Sulfate Stimulus Tamoxifen Testing Therapeutic United States National Institutes of Health Validation acute infection antimicrobial base chronic infection clinical center cohort combat dextran sulfate sodium induced colitis experimental study extracellular gastrointestinal gene therapy improved in vivo insight malignant breast neoplasm neutrophil new therapeutic target novel pathogen pathogenic bacteria pre-clinical pre-clinical research recurrent infection respiratory response targeted treatment

项目摘要

Project Summary In addition to the classical mode of phagocytosis and intracellular oxidative killing of pathogens, a recently discovered antimicrobial function of neutrophils is the formation of extracellular traps (Neutrophil Extracellular Traps, NETs), which can trap and kill pathogens extracellularly. As NET formation (NETosis) generally requires reactive oxygen species (ROS) generation, we and others have found that neutrophils from Chronic Granulomatous Diseases (CGD) patients and Gp91phox-/- CGD mice with mutations in NADPH oxidase complex exhibit impaired NET generation in-vitro and in-vivo in response to various stimuli and pulmonary bacterial infection. We recently reported that Tamoxifen (TMX), an FDA approved selective estrogen receptor (ER) modifier for treatment of breast cancer, induces antimicrobial NETs in CGD neutrophils in a ROS independent manner. We further showed that activation of autophagy is necessary and sufficient to induce TMX-mediated NETs. In addition to this seminal report, the premise of the proposed research is derived from our preliminary data indicating a novel pathway of ROS-and ER-independent NETosis by TMX via a non-canonical autophagy activation. The two proposed specific aims will establish TMX as NET-inducing agent with antimicrobial and anti- inflammatory effect in preclinical murine CGD and human CGD neutrophils (Aim 1); and elucidate TMX-mediated non-canonical autophagy signaling pathway in neutrophils that culminates in disintegration of nuclear lamina to facilitate the release of NETs (Aim 2). Our studies provide important mechanistic insights into a novel autophagy pathway activated by TMX which will have implications not only for NET research but also for exploiting autophagy and NETs to treat infectious and autoimmune diseases. By leveraging neutrophils from a well- characterized cohort of CGD patients at NIH Clinical Center, these studies also present an exciting opportunity for preclinical testing of TMX in CGD to restore antimicrobial function of neutrophils to combat pneumonic bacterial infections, frequently observed in these patients.

项目摘要除了经典的吞噬作用和病原体细胞内氧化杀死的模式外，嗜中性粒细胞发现的抗菌功能是细胞外陷阱的形成（细胞外粒细胞外陷阱，网），可以捕获并杀死细胞质的病原体。由于净形成（Netosis）通常需要活性氧（ROS）产生，我们和其他人发现慢性中性粒细胞肉芽肿性疾病（CGD）患者和gp91phox - / - CGD小鼠在NADPH氧化酶复合物中具有突变响应各种刺激和肺细菌，表现出净产生净产生和体内的净产生。感染。我们最近报道了FDA批准的选择性雌激素受体（ER）的他莫昔芬（TMX）用于治疗乳腺癌的修饰剂，在ROS独立的CGD中性粒细胞中诱导抗菌网方式。我们进一步表明，自噬的激活是必要的，足以诱导TMX介导网。除了这份开创性的报告外，拟议的研究的前提还来自我们的初步数据表明TMX通过非典型自噬的N Netosis的新途径是新的途径激活。提出的两个特定目的将建立TMX作为抗菌和抗抗菌剂的网络诱导剂临床前鼠CGD和人CGD中性粒细胞中的炎症作用（AIM 1）；并阐明TMX介导的中性粒细胞中的非典型自噬信号通路，最终导致核层中瓦解至促进网释放（AIM 2）。我们的研究为新型自噬提供了重要的机械见解 TMX激活的途径不仅对净研究有影响，而且对利用有影响自噬和网络治疗传染性和自身免疫性疾病。通过利用中性粒细胞这些研究表征了NIH临床中心的CGD患者队列，也带来了令人兴奋的机会用于CGD中TMX的临床前测试，以恢复中性粒细胞的抗菌功能以对抗肺炎细菌感染，在这些患者中经常观察到。