Pin1 regulation of prosurvival signalling in eosinophils

Pin1 对嗜酸性粒细胞中促生存信号的调节

• 批准号: 7667752
• 负责人: James S Malter
• 金额: $ 37.13万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-05 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7667752
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adrenal Cortex Hormones; Affinity; Allergens; Animal Model; Apoptosis; Apoptotic; Asthma; Binding; Binding Proteins; Biology; Breathing; Cell Cycle Progression; Cell Surface Receptors; Cells; Chronic; Cyclophilin A; Data; Development; Enzymes; Exposure to; Family; Fibrosis; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Factor; Immune; Inflammation; Interleukin-3; Interleukin-5; Isomerase; Life; Lung; MAP Kinase Gene; Mediating; Messenger RNA; Metabolism; Molecular Conformation; Morbidity - disease rate; Nerve Degeneration; Participant; Pathway interactions; Peptides; Peptidylprolyl Isomerase; Pharmaceutical Preparations; Phenotype; Phosphorylation; Phosphoserine; Phosphothreonine; Phosphotransferases; Pneumonia; Process; Production; Proline; Proteins; Pulmonary Eosinophilia; RNA Decay; Regulation; Resistance; Respiratory physiology; Role; Signal Transduction; Tacrolimus Binding Protein 1A; Tissues; airway remodeling; chemokine; cis trans isomerization; cytokine; drug development; eosinophil; mRNA Stability; parvulin; prevent; pro-caspase-8; public health relevance; repaired; response; tumorigenesis

DESCRIPTION (provided by applicant): Eosinophilic pulmonary inflammation is a cardinal feature of asthma. Once in the lung, eosinophils (Eos) show an activated phenotype and become resistant to apoptosis after exposure to prosurvival cytokines such as GM-CSF. Long lived Eos contribute to tissue damage and facilitate the development of submucosal, bronchial fibrosis and airway remodeling. Therefore, suppression of GM-CSF production or its prosurvival signaling could reduce pulmonary eosinophilia and the long-term morbidity of asthma. GM-CSF released by activated Eos binds to a heterodimeric, cell surface receptor which activates multiple prosurvival cascades involving PI-3K, MAPK and Syk. How these pathways modulate Eos survival are largely unknown. Recently, we identified the peptidyl-prolyl isomerase (PPIase), Pin1, as a critical participant in GM-CSF mRNA metabolism as well as subsequent prosurvival signaling in Eos. Pin1 binds to and catalyzes the cis-trans isomerization of phosphoserine-proline or phosphothreonine-proline (Ser/Thr-Pro) peptide bonds. Isomerization of target proteins alters their conformation, function or stability. We now show that Pin1's isomerase activity is required for Eos survival in at least 2 ways. First, Pin1 controls the production of prosurvival cytokines by Eos by regulating the stability of GM-CSF mRNA. Pin1 binds to and directly controls the affinity of critical mRNA binding proteins for both GM-CSF mRNA and the RNA decay machinery in cells. Secondly, Pin1 is essential for the prosurvival effects of GM-CSF by directly interacting with multiple apoptotic effectors including Bax, PKC and procaspase 8. Therefore, we hypothesize that Pin1 is a critical, signaling intermediate which controls eosinophil survival through the regulation of GM-CSF production and GM-CSF prosurvival signaling. We therefore propose to: 1. Identify how Pin1 activity is regulated by GM-CSF mediated signaling. 2. Determine how Pin1 regulates the function of the GM-CSF mRNA binding protein, AUF1. 3. Characterize how Pin1 modulates the prosurvival effects of GM-CSF. 4. Determine if Pin1 blockade can reduce eosinophilic inflammation and preserve lung function in synergy with inhaled corticosteroids in animal models of asthma. In aggregate these studies will further our understanding of Eos biology in asthma. PUBLIC HEALTH RELEVANCE. Completion of the proposed studies will help understand how eosinophils die when growth factors are removed and potentially pave the way for the development of drugs which can accelerate that process. Such drugs could be useful for the treatment of chronic asthma.

描述（由申请人提供）：嗜酸性粒细胞性肺部炎症是哮喘的主要特征。一旦进入肺部，嗜酸性粒细胞（Eos）在暴露于促生存细胞因子（如GM-CSF）后表现出活化表型并对凋亡产生抗性。长寿命的Eos有助于组织损伤，促进粘膜下、支气管纤维化和气道重塑的发展。因此，抑制GM-CSF的产生或其促生存信号可以减少肺嗜酸性粒细胞增多和哮喘的长期发病率。被激活的Eos释放的GM-CSF与异二聚体细胞表面受体结合，激活包括PI-3K、MAPK和Syk在内的多个促生存级联反应。这些途径如何调节Eos的生存在很大程度上是未知的。最近，我们发现肽基脯氨酸异构酶（PPIase） Pin1是Eos中GM-CSF mRNA代谢和随后的促生存信号传导的关键参与者。Pin1结合并催化磷酸丝氨酸-脯氨酸或磷酸苏氨酸-脯氨酸（Ser/Thr-Pro）肽键的顺-反异构化。靶蛋白的异构化改变了它们的构象、功能或稳定性。我们现在表明Pin1的异构酶活性至少在两个方面是Eos存活所必需的。首先，Pin1通过调节GM-CSF mRNA的稳定性，通过Eos控制促生存细胞因子的产生。Pin1结合并直接控制关键mRNA结合蛋白对细胞中GM-CSF mRNA和RNA衰变机制的亲和力。其次，Pin1通过直接与Bax、PKC和procaspase 8等多种凋亡效应因子相互作用，对GM-CSF的促存活作用至关重要。因此，我们假设Pin1是一种关键的信号传导介质，通过调节GM-CSF的产生和GM-CSF促生存信号传导来控制嗜酸性粒细胞的生存。因此，我们建议：确定Pin1活性如何被GM-CSF介导的信号调节。2. 确定Pin1如何调节GM-CSF mRNA结合蛋白AUF1的功能。3. 描述Pin1如何调节GM-CSF的促生存作用。4. 在哮喘动物模型中，确定Pin1阻断是否可以减少嗜酸性粒细胞炎症并与吸入皮质类固醇协同保护肺功能。总的来说，这些研究将进一步加深我们对Eos生物学在哮喘中的理解。公共卫生相关性。拟议研究的完成将有助于了解当生长因子被移除时嗜酸性粒细胞是如何死亡的，并可能为开发加速这一过程的药物铺平道路。这类药物可能对治疗慢性哮喘有用。