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: 7533391
• 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/7533391
• 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; Object Attachment; Participant; Pathway interactions; Peptides; Peptidylprolyl Isomerase; Pharmaceutical Preparations; Phenotype; Phosphorylation; Phosphoserine; Phosphothreonine; Phosphotransferases; Pneumonia; Process; Production; Proline; Proteins; Public Health; 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; 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，嗜酸性粒细胞（Eos）表现出活化的表型，并在暴露于促生存细胞因子（如GM-CSF）后对凋亡产生抗性。长寿命的Eos有助于组织损伤并促进粘膜下、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。由活化的Eos释放的GM-CSF结合到异源二聚体的细胞表面受体，其活化涉及PI-3 K、MAPK和Syk的多个促存活级联。这些通路如何调节Eos存活在很大程度上是未知的。最近，我们确定了肽基脯氨酰异构酶（PPIase），Pin 1，作为一个关键的参与者在GM-CSF mRNA代谢以及随后的促生存信号在Eos。Pin 1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，Pin 1的异构酶活性所需的Eos生存至少有2种方式。首先，Pin 1通过调节GM-CSF mRNA的稳定性来控制Eos产生促生存细胞因子。Pin 1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。第二，Pin 1通过直接与多种凋亡效应物（包括Bax、PKC和procaspase 8）相互作用而对GM-CSF的促存活作用是必需的。因此，我们假设Pin 1是一个关键的信号中间体，通过调节GM-CSF的产生和GM-CSF促生存信号来控制嗜酸性粒细胞的存活。因此，我们建议：确定Pin 1活性是如何通过GM-CSF介导的信号调节的。2.确定Pin 1如何调节GM-CSF mRNA结合蛋白AUF 1的功能。3.描述Pin 1如何调节GM-CSF的促生存作用。4.在哮喘动物模型中，确定Pin 1阻断是否可以减少嗜酸性粒细胞炎症并与吸入性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哮喘中Eos生物学的理解。公共卫生相关性。完成拟议的研究将有助于了解当生长因子被去除时嗜酸性粒细胞是如何死亡的，并可能为开发可以加速这一过程的药物铺平道路。这些药物可能对治疗慢性哮喘有用。