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

描述(申请人提供)：超过2400万美国人患有哮喘，它已经成为一种慢性呼吸道炎症性疾病，以可逆性气流阻塞和支气管痉挛为特征，并伴有喘息、咳嗽、呼吸急促和胸闷的症状。与慢性阻塞性肺疾病(COPD)或肺气肿不同，哮喘患者的呼吸道阻塞通常是可逆的，但如果不进行治疗，可能会由于呼吸道重塑而导致不可逆转的气流阻塞。治疗哮喘患者每年的费用超过560亿美元，通常包括药物，包括放松呼吸道平滑肌肉的支气管扩张剂和减少呼吸道炎症的抗炎药。在这项提案中，我们专注于一种潜在的治疗哮喘的新疗法：COG化合物，它拮抗蛋白磷酸酶2A的抑制剂#2(I2PP2A或SET)，导致PP2A的重新激活和减轻炎症(Christensen等人)。2011年)。Levine及其同事最近的文献表明，1)载脂蛋白-E的表达与类固醇的反应性有关，2)持续给予COG130(一种源自残基130-149的载脂蛋白E的模拟肽)可显著降低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，3)COG130治疗的这种平喘治疗效果需要apoE和COG130的低密度脂蛋白受体(LDLR)(姚等人)。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模拟化合物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.