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: 7810685
• 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/7810685
• 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; eosinophilic inflammation; 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）：嗜酸性肺炎症是哮喘的基本特征。进入肺部后，嗜酸性粒细胞（EOS）显示出激活的表型，并在暴露于诸如GM-CSF之类的Proservival细胞因子（例如GM-CSF）后对凋亡具有抗性。长期以来的EOS有助于组织损伤，并促进粘膜下粘膜，支气管纤维化和气道重塑的发展。因此，抑制GM-CSF产生或其生存信号传导可以减少肺嗜酸性粒细胞和哮喘的长期发病率。由激活的EOS释放的GM-CSF与异二聚体，细胞表面受体结合，该细胞表面受体激活涉及PI-3K，MAPK和SYK的多个Proservival级联反应。这些途径如何调节EOS存活率在很大程度上未知。最近，我们确定了肽基 - 蛋白酶异构酶（PPIASE），PIN1，是GM-CSF mRNA代谢的关键参与者，以及随后在EOS中的Prosurvival信号传导。 PIN1与磷serine--磷酸或磷酸磷酸磷酸磷酸（Ser/Thr-Pro）肽键的顺式传播异构化结合并催化。靶蛋白的异构化改变其构象，功能或稳定性。我们现在表明，EOS生存至少2种方式需要PIN1的异构酶活性。首先，PIN1通过调节GM-CSF mRNA的稳定性来控制EOS的生存细胞因子的产生。 PIN1结合并直接控制临界mRNA结合蛋白对GM-CSF mRNA和细胞中RNA衰变机械的亲和力。其次，PIN1对于GM-CSF的Prosurvival效应至关重要，它通过与多个凋亡效应子（包括Bax，PKC和Procaspase 8）直接相互作用。因此，我们假设PIN1是控制嗜酸性粒细胞的关键，信号中间体，它通过调节GM-CSF生产和GM-CSF Prosurvialts的调节来控制嗜酸性粒细胞的存活。因此，我们建议：1。确定PIN1活性如何受到GM-CSF介导的信号传导调节。 2。确定PIN1如何调节GM-CSF mRNA结合蛋白AUF1的功能。 3。表征PIN1如何调节GM-CSF的生存效应。 4。确定PIN1阻断是否可以减少嗜酸性炎症，并保留与哮喘动物模型中吸入的皮质类固醇协同作用的肺功能。在总体上，这些研究将进一步了解哮喘中的EOS生物学。公共卫生相关性。拟议的研究的完成将有助于了解嗜酸性粒细胞在去除生长因子时如何死亡，并有可能为可以加速该过程的药物开发铺平道路。这种药物可能对治疗慢性哮喘有用。