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

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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.