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

描述（由申请人提供）：超过2400万美国人患有哮喘，哮喘已成为一种以可逆性气流阻塞和支气管痉挛为特征的气道慢性炎症性疾病，并伴有喘息、咳嗽、呼吸短促和胸闷等症状。与慢性阻塞性肺疾病（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，可能导致气道重塑导致不可逆转的气流阻塞。治疗哮喘患者每年花费超过560亿美元，通常包括支气管扩张剂（可以放松气道平滑肌）和消炎药（可以减少气道炎症）。在这项建议中，我们专注于一种潜在的哮喘新疗法：cog化合物，它可以拮抗蛋白磷酸酶2A （I2PP2A或SET）的抑制剂#2，导致PP2A的再激活和炎症的减少（Christensen等人，2011）。Levine及其同事最近的文献表明，1)载脂蛋白e的表达与类固醇反应性有关，2)在尘螨诱导的哮喘小鼠模型中，持续递送COG130（一种从残基130-149衍生的载脂蛋白e的肽模拟物）可显著降低哮喘症状和细胞因子水平。3) apoE和COG130的低密度脂蛋白受体（LDLR）是COG130治疗的抗哮喘治疗效果所必需的（Yao et al. 2010）。基于这些报告，我们现在建议进行实验，以支持COG/载脂蛋白e模拟化合物的开发，作为哮喘的治疗方法。

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.