Immunosuppression in Acute Lung Injury

急性肺损伤中的免疫抑制

基本信息

批准号：
10631050
负责人：
Rama K Mallampalli
金额：
$ 233.56万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-03 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10631050
关键词：
Acetyltransferase Acute Lung Injury Acute Respiratory Distress Syndrome Alveolar Amino Acids Animal Model Bacterial Infections Bacterial Pneumonia Biological Markers Biology CD8B1 gene Cardiolipins Cell Death Cell Death Induction Cell Nucleus Cell Survival Cell physiology Cells Cessation of life Chemotaxis Clinical Complement Cytokine Gene Defect Degradation Pathway Development Disease Effector Cell Environment Epigenetic Process Epithelial Cells Epithelium Equilibrium Evolution FRAP1 gene Functional disorder Gene Expression Genes Gram-Negative Bacterial Infections Host Defense Human Hydroxyeicosatetraenoic Acids IL10 gene IRF1 gene Immune Immunity Immunosuppression Impairment In Vitro Inflammation Inflammatory Innate Immune Response Interleukin-10 Ligands Link Lipids Liver Lung Lung infections Lymphocyte Macrophage Mediating Mediator Mitochondria Modeling Molecular Molecular Target Multiple Organ Failure Myelogenous Myeloid Cells Myeloid-derived suppressor cells NF-kappa B Natural Immunity Oxidation-Reduction PPAR gamma Paraoxonase-2 Pathogenesis Pathway interactions Patients Phagocytes Phagocytosis Pharmacotherapy Phase Phenotype Phosphatidylethanolamine Phospholipids Pneumonia Population Program Research Project Grants Proteins Reactive Oxygen Species Research Personnel Respiratory Failure Risk Factors Scientific Inquiry Secondary to Sepsis Services Signal Pathway Signal Transduction System Testing Therapeutic Intervention Time Translating Ubiquitin Virulent biobank bioimaging body system chemokine chromatin remodeling clinically relevant combinatorial cytokine design histone modification human subject in vivo inhibitor innate immune function insight lipidomics lung injury mortality novel novel therapeutics oxidation pathogenic bacteria pathogenic microbe patient subsets physiologic stressor preservation programs response small molecule inhibitor tool ubiquitin-protein ligase

项目摘要

Acute respiratory distress syndrome (ARDS) is most commonly due to severe pneumonia or sepsis. Decades of intense study have focused on the initial inflammatory phase of ARDS, and yet mortality rates for ARDS are still very high because newer pharmocotherapies have not emerged. In this Program Project Grant competing renewal application, we have assembled a team of world-class leaders with complementary expertise to investigate a new pathophysiologic model that challenges the existing concept that ARDS is solely a hyper-inflammatory disorder. In this model, we will investigate a novel concept that in ARDS, immunosuppression is a signature manifestation in a subset of patients secondary to unique, combinatorial pathways that modulate epithelial and myeloid cell viability and innate immune function. We hypothesize that immune suppression occurs via chromatin remodeling and ubiquitin- degradative pathways (Project 1), through a set of distinct cell death pathways including a new form of oxidation driven, non-apoptotic cell death termed ferroptosis (Project 2), through a phenotypic shift from loss of crucial host-protective lymphocytes (CD8+, MAIT cells) to immunosuppressive myeloid cells (Project 3), and oxidation-mediated impairment of macrophage bacterial killing and phagocytosis (Project 4). To evaluate this hypothesis, investigators will employ state-of-art molecular, cell, human-based systems, and lipidomic tools. These approaches will be translated to complementary 2- hit models of lung injury and immunosuppression and analysis in ARDS human subjects. The Program will be supported by two highly interactive Cores with expertise in human biorepository services and bioimaging. Execution of these studies will provide a paradigm-changing conceptual model for ARDS pathogenesis that serves as a basis for therapeutic intervention and providing a new and sustained field of scientific inquiry in lung biology.

急性呼吸窘迫综合征 (ARDS) 最常见的原因是严重的肺炎或败血症。数十年的深入研究集中于最初的炎症 ARDS 的阶段，但 ARDS 的死亡率仍然非常高，因为较新的药物疗法尚未出现。在本计划中，项目补助金竞争更新应用方面，我们组建了一支由世界级领导者组成的团队，互补性强研究挑战现有病理生理学模型的专业知识 ARDS 仅仅是一种高炎症性疾病。在这个模型中，我们将研究一个新概念：免疫抑制是 ARDS 的一个特征继发于独特的组合途径的一小部分患者的表现调节上皮细胞和骨髓细胞活力以及先天免疫功能。我们假设免疫抑制是通过染色质重塑和泛素发生的降解途径（项目 1），通过一组不同的细胞死亡途径，包括一种新形式的氧化驱动的非凋亡细胞死亡，称为铁死亡（项目 2），通过关键宿主保护性淋巴细胞（CD8+、MAIT 细胞）到免疫抑制性骨髓细胞（项目 3），以及氧化介导的巨噬细胞杀灭细菌和吞噬作用受损（项目 4）。评估根据这一假设，研究人员将采用最先进的分子、细胞、人类基础系统和脂质组学工具。这些方法将转化为互补的 2- ARDS 人类受试者的肺损伤和免疫抑制模型及分析。该计划将得到两个具有人类专业知识的高度互动核心的支持生物样本库服务和生物成像。这些研究的执行将提供 ARDS 发病机制的范式改变概念模型，作为基础治疗干预并提供一个新的、持续的科学探究领域肺生物学。

项目成果

期刊论文数量（78）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Glycogen synthase kinase-3β stabilizes the interleukin (IL)-22 receptor from proteasomal degradation in murine lung epithelia.

糖原合酶激酶-3β 稳定白细胞介素 (IL)-22 受体免受小鼠肺上皮蛋白酶体降解。

DOI：
发表时间：
2014-06-20
期刊：
影响因子：
0
作者：
Weathington, Nathaniel M;Snavely, Courtney A;Chen, Bill B;Zhao, Jing;Zhao, Yutong;Mallampalli, Rama K
通讯作者：
Mallampalli, Rama K

The acute respiratory distress syndrome: from mechanism to translation.

急性呼吸窘迫综合征：从机制到转化。

DOI：
发表时间：
2015-02-01
期刊：
影响因子：
0
作者：
Han, SeungHye;Mallampalli, Rama K
通讯作者：
Mallampalli, Rama K

Payload drug vs. nanocarrier biodegradation by myeloperoxidase- and peroxynitrite-mediated oxidations: pharmacokinetic implications.

有效负载药物与纳米载体通过髓过氧化物酶和过氧亚硝酸盐介导的氧化进行生物降解：药代动力学影响。

DOI：
发表时间：
2015-05-21
期刊：
影响因子：
6.7
作者：
Seo, Wanji;Kapralov, Alexandr A;Shurin, Galina V;Shurin, Michael R;Kagan, Valerian E;Star, Alexander
通讯作者：
Star, Alexander

Lipopolysaccharide Primes the NALP3 Inflammasome by Inhibiting Its Ubiquitination and Degradation Mediated by the SCFFBXL2 E3 Ligase.

脂多糖通过抑制 SCFFBXL2 E3 连接酶介导的 NALP3 炎症体泛素化和降解来启动 NALP3 炎症体。

DOI：
发表时间：
2015-07-17
期刊：
影响因子：
0
作者：
Han, SeungHye;Lear, Travis B;Jerome, Jacob A;Rajbhandari, Shristi;Snavely, Courtney A;Gulick, Dexter L;Gibson, Kevin F;Zou, Chunbin;Chen, Bill B;Mallampalli, Rama K
通讯作者：
Mallampalli, Rama K

Cleavage of Signal Regulatory Protein α (SIRPα) Enhances Inflammatory Signaling.

信号调节蛋白α (SIRPα) 的裂解增强炎症信号传导。