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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（由申请人提供）：超过2400万美国人患有哮喘，其已成为气道的慢性炎症性疾病，特征在于可逆的气流阻塞和支气管痉挛以及喘息、咳嗽、呼吸短促和胸闷的症状。与慢性阻塞性肺病（COPD）或肺气肿不同，哮喘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。治疗哮喘患者每年花费超过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。在该提案中，我们专注于一种潜在的哮喘新疗法：拮抗蛋白磷酸酶2A（I2 PP 2A或SET）抑制剂#2的COG化合物，导致PP 2A再活化和炎症减轻（Christensen et al. 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）持续给予COG 130（衍生自残基130-149的载脂蛋白-E的肽模拟物）显著降低了屋尘螨诱导的哮喘小鼠模型中的哮喘症状和细胞因子水平，和3）apoE和COG 130的低密度脂蛋白受体（LDLR）是COG 130治疗的这种抗哮喘治疗作用所必需的（Yao et al.2010）。基于这些报告，我们现在建议进行实验，以支持开发COG/载脂蛋白-E-模拟物化合物作为哮喘的治疗性治疗。