Pin1 regulation of prosurvival signalling in eosinophils

Pin1 对嗜酸性粒细胞中促生存信号的调节

基本信息

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
项目类别：
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

项目摘要

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）：嗜酸性肺部炎症是哮喘的主要特征。一旦进入肺部，嗜酸性粒细胞 (Eos) 就会表现出激活的表型，并在暴露于 GM-CSF 等促存活细胞因子后对细胞凋亡产生抵抗力。长寿命的 Eos 会导致组织损伤，并促进粘膜下层、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传导可以减少肺嗜酸性粒细胞增多和哮喘的长期发病率。激活的 Eos 释放的 GM-CSF 与异二聚体细胞表面受体结合，激活涉及 PI-3K、MAPK 和 Syk 的多个促生存级联反应。这些途径如何调节 Eos 的存活很大程度上尚不清楚。最近，我们发现肽基脯氨酰异构酶 (PPIase) Pin1 是 GM-CSF mRNA 代谢以及 Eos 中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。靶蛋白的异构化会改变其构象、功能或稳定性。我们现在证明 Pin1 的异构酶活性至少通过两种方式是 Eos 生存所必需的。首先，Pin1 通过调节 GM-CSF mRNA 的稳定性来控制 Eos 促存活细胞因子的产生。 Pin1 结合并直接控制细胞中 GM-CSF mRNA 和 RNA 降解机制的关键 mRNA 结合蛋白的亲和力。其次，Pin1 通过直接与包括 Bax、PKC 和 procaspase 8 在内的多种凋亡效应子相互作用，对于 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中间体，通过调节 GM-CSF 来控制嗜酸性粒细胞的存活。 CSF 产生和 GM-CSF 促生存信号传导。因此，我们建议： 1. 确定 Pin1 活性如何受 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. 描述 Pin1 如何调节 GM-CSF 的促生存作用。 4. 确定 Pin1 阻断是否可以与哮喘动物模型中的吸入皮质类固醇协同减少嗜酸性粒细胞炎症并保护肺功能。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如何死亡，并可能为开发可以加速这一过程的药物铺平道路。此类药物可用于治疗慢性哮喘。