Inhibitor #2 of Protein Phosphatase 2A (I2PP2A) and Asthma

抑制剂

基本信息

批准号：
8644994
负责人：
MICHAEL PETER VITEK
金额：
$ 26.82万
依托单位：
COGNOSCI, INC.
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：
2014-02-06 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8644994
关键词：
Adrenal Cortex Hormones Affect Air American Animals Anti-Asthmatic Agents Anti-Inflammatory Agents Anti-inflammatory Apolipoprotein E Asthma Back Breathing Bronchial Spasm Bronchoalveolar Lavage Fluid Bronchodilator Agents Canis familiaris Cell model Cells Chest Chronic Chronic Obstructive Airway Disease Clinic Clinical Coughing Data Detection Development Dexamethasone Disease Dose Extrinsic asthma Fostering Goblet Cells Grant Healthcare Hyperplasia IgE Inflammation Inflammation Mediators Inflammatory Interleukin-2 Interleukin-4 Investigational Drugs Investigational New Drug Application Lead Left Link Literature Low Density Lipoprotein Receptor Lung Marketing Maximum Tolerated Dose Measures Medicine Modeling Mus Obstruction Patients Peptides Pharmaceutical Preparations Phase Phosphoric Monoester Hydrolases Plasma Protein phosphatase Protocols documentation Publishing Pulmonary Emphysema Pyroglyphidae Rattus Reporting Research Resistance Serum Shortness of Breath Small Business Innovation Research Grant Smooth Muscle Steroid Resistance Steroids Symptoms Testing Therapeutic Therapeutic Agents Therapeutic Effect Time Toxic effect U937 Cells United States United States Food and Drug Administration Western Blotting Wheezing Work airway hyperresponsiveness airway inflammation airway obstruction airway remodeling apolipoprotein E-1 base cost cytokine eosinophil fluticasone functional restoration good laboratory practice inhibitor/antagonist macrophage methacholine mimetics mouse model neutrophil novel protein phosphatase 2A inhibitor 2 public health relevance receptor research study response safety study

项目摘要

DESCRIPTION (provided by applicant): Over 24 million Americans suffer from asthma, which has become a chronic inflammatory disease of the airways characterized by reversible airflow obstruction and bronchospasm together with symptoms of wheezing, coughing, shortness of breath, and chest tightness. Unlike chronic obstructive pulmonary disease (COPD) or emphysema, airway obstruction is usually reversible in asthma, but if left untreated, can lead to irreversible air-flow obstruction due to airway remodeling. Treating asthma patients costs over $56 billion each year and typically consists of medications including bronchodilators that relax the smooth muscles in the airways and anti-inflammatories to reduce airway inflammation. In this proposal, we are focused on a potentially novel therapy for asthma: COG-compounds that antagonize inhibitor #2 of Protein Phosphatase 2A (I2PP2A or SET) leading to reactivation of PP2A and reduction of inflammation (Christensen et al. 2011). Recent literature by Levine and colleagues suggests that 1) apolipoprotein-E expression is associated with steroid responsiveness, 2) that continuous delivery of COG130 (a peptide mimetic of apolipoprotein-E derived from residues 130-149) significantly reduced asthma symptoms and cytokine levels in a house dust mite-induced mouse model of asthma, and 3) that the Low Density Lipoprotein receptor (LDLR) for apoE and for COG130 was required for this anti-asthmatic therapeutic effect of COG130 treatment (Yao et al. 2010). Based on these reports, we now propose to perform experiments to support development of COG/apolipoprotein-E-mimetic compounds as a therapeutic treatment for asthma.

描述（申请人提供）：超过 2400 万美国人患有哮喘，它已成为一种慢性气道炎症性疾病，其特征是可逆性气流阻塞和支气管痉挛，并伴有喘息、咳嗽、气短和胸闷症状。与慢性阻塞性肺病 (COPD) 或肺气肿不同，哮喘中的气道阻塞通常是可逆的，但如果不及时治疗，可能会因气道重塑而导致不可逆的气流阻塞。每年治疗哮喘患者的费用超过 560 亿美元，通常包括药物，包括放松气道平滑肌的支气管扩张剂和减少气道炎症的抗炎药。在本提案中，我们重点关注一种潜在的哮喘新疗法：COG 化合物，它拮抗蛋白磷酸酶 2A（I2PP2A 或 SET）的抑制剂 #2，导致 PP2A 重新激活并减少炎症（Christensen 等人，2011）。 Levine 及其同事最近的文献表明，1) 载脂蛋白-E 表达与类固醇反应性相关，2) 持续递送 COG130（源自残基 130-149 的载脂蛋白-E 肽模拟物）可显着减轻哮喘症状和细胞因子水平屋尘螨诱发的哮喘小鼠模型，3) apoE 和 COG130 的低密度脂蛋白受体 (LDLR) 是COG130 治疗的这种抗哮喘治疗效果（Yao 等，2010）。基于这些报告，我们现在建议进行实验来支持开发 COG/载脂蛋白-E-模拟化合物作为哮喘的治疗方法。