SCF-based Ubiquitin E3 Ligases in the Pathobiology of Pneumonia

基于 SCF 的泛素 E3 连接在肺炎病理学中的应用

基本信息

批准号：
9353268
负责人：
Rama K Mallampalli
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
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：
2014-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9353268
关键词：
Acute Acute Lung Injury Adrenal Cortex Hormones Anti-Inflammatory Agents Attenuated Bacterial Infections Bacterial Pneumonia Binding Calcium Calmodulin Cartoons Cause of Death Cells Cessation of life Cytokine Signaling Data Development Disease Drosophila pros protein Effector Cell Epithelium F Box Domain F-Box Proteins Failure Family Generations Hospitals Human Humira Immune Immune response Impairment Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Interleukin-1 Intervention Invaded Lead Long-Term Care Lung Mediating Modeling Molecular Molecular Models Molecular Profiling Morbidity - disease rate Multi-Drug Resistance Mutation Natural Immunity Necrosis Orphan Pathogenesis Pathway interactions Patients Peripheral Blood Mononuclear Cell Phase III Clinical Trials Pneumonia Point Mutation Population Production Protein Family Proteins Pulmonary Edema Regulation Role Sentinel Sepsis Severities Shock Signal Transduction Surface System TLR4 gene TNF Receptor-Associated Factors TNF gene Testing Therapeutic Intervention Tissues Transcriptional Activation Ubiquitination Veterans Virulent antimicrobial base cytokine design human subject immunoreactivity in vivo infliximab inhibitor/antagonist link protein loss of function lung injury molecular modeling monocyte mortality mouse model mutant novel novel strategies novel therapeutics pathogen protein degradation public health relevance receptor response sensor small molecule small molecule inhibitor ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Pheumonia is a leading cause of death among Veterans. A hallmark of pheumonia is acute lung injury resulting from a profound release of host cell cytokines. The tumor necrosis factor receptor associated factor (TRAF) proteins are critical in mediating cytokines responses, but little is known regarding their molecular regulation. Here we show that a ubiquitin E3 ligase subunit, termed F box protein FBXL2, serves as a sentinel inhibitor that mediates disposal of TRAF proteins to impair cytokines secretion in pro-inflammatory cells. Further, we discovered that a relatively new protein, termed F box protein FBX03, targets FBXL2 for degradation thereby stimulating cytokine release. FBX03 harbors a bacterial-like molecular signature that led to the development of a potent anti-inflammatory agent, BC1215. A loss-of-function naturally occurring FBX03 mutation was also identified in human subjects that lack ability to robustly express cytokines. Thus, in this proposal, we will test the hypothesis that antagonism or mutation of FBX03 results in reduced severity of acute lung injury from pneumonia by preserving levels of FBXL2, which in turn mediates degradation of TRAF proteins that are pro-inflammatory. To Evaluate this hypothesis,we will determine if during experimental pneumonia FBXO3 stimulates cytokine release by stabilizing TRAF proteins via degradation of the TRAF inhibitor, FBXL2 (Aim 1), determine if a novel small molecule FBXO3 antagonist, BC1215, lessens severity of acute lung injury during experimental pneumonia (Aim 2), and determine if a naturally occurring FBXO3 point mutation reduces severity of acute lung injury during pneumonia in hospitalized Veterans (Aim 3). In summary, this application unveils a new molecular model of innate immunity as it relates to cytokine signaling. Execution of these studies will lay the groundwork for a fundamental conceptual advance in the pathobiology of inflammation that sets the stage for a new translational initiative in Veterans with pneumonia.

描述（由申请人提供）：肺炎是退伍军人死亡的主要原因。肺炎的一个标志是宿主细胞细胞因子大量释放导致的急性肺损伤。肿瘤坏死因子受体相关因子 (TRAF) 蛋白在介导细胞因子反应中至关重要，但对其分子调控知之甚少。在这里，我们展示了泛素 E3 连接酶亚基（称为 F 盒蛋白 FBXL2）作为前哨抑制剂，介导 TRAF 蛋白的处理，从而损害促炎细胞中的细胞因子分泌。此外，我们发现一种相对较新的蛋白质，称为 F 盒蛋白 FBX03，以 FBXL2 为目标进行降解，从而刺激细胞因子释放。 FBX03 具有类似细菌的分子特征，从而导致了强效抗炎剂 BC1215 的开发。在缺乏稳健表达细胞因子能力的人类受试者中也发现了自然发生的功能丧失 FBX03 突变。因此，在本提案中，我们将测试以下假设：FBX03 的拮抗或突变通过保持 FBXL2 的水平来降低肺炎引起的急性肺损伤的严重程度，而 FBXL2 反过来又介导促炎性 TRAF 蛋白的降解。为了评估这一假设，我们将确定在实验性肺炎期间，FBXO3 是否通过降解 TRAF 抑制剂 FBXL2 来稳定 TRAF 蛋白，从而刺激细胞因子释放（目标 1），确定新型小分子 FBXO3 拮抗剂 BC1215 是否可以减轻急性肺损伤的严重程度实验性肺炎期间（目标 2），并确定自然发生的 FBXO3 点突变是否会降低住院退伍军人肺炎期间急性肺损伤的严重程度（目标3）。总之，该应用揭示了一种与细胞因子信号传导相关的先天免疫的新分子模型。这些研究的执行将为炎症病理学的基本概念进步奠定基础，从而为患有肺炎的退伍军人的新转化计划奠定基础。