Explore the Role of AMCase by RNAi Targeting for Developing Asthma Therapy

Asthma, a chronic Th2-mediated inflammatory disease, is characterized by airway hyperresponsiveness and inflammation. Growing evidence suggests that an increased expression of acidic mammalian chitinase (AMCase) may play a role in the pathogenesis of asthma. In the present study, we hypothesize that specific suppression of elevated AMCase results in reduced eosinophilia and Th2-mediated airway inflammation in a mouse model of asthma. We propose to investigate the biology and the RNAi-based therapeutic implications of targeting AMCase for asthma therapy. Specific aims are as followed: 1. to determine whether the elevation of AMCase expression directly correlated with the induction and/or the severity of asthmatic disease 2. to develop the high efficient recombinant adeno-associated virus expressing short hairpin RNA (rAAV-shRNA) against AMCase 3. to evaluate whether targeting AMCase by siRNA directly makes AMCase levels, eosinophilia (or the absolute number of eosinophils in the BAL fluid), IgE, and IL-13 production decrease as well as the inhibitory effects on mucus production or airway hyperresponsiveness 4. to identify the mechanisms of targeting AMCase resulting in the inhibition the allergic responses 5. to evaluate the duration of the suppressive effects by targeting AMCase or whether the duration might be limited by the targeting method selected. 6. to identify the target subtract of AMCase within the lung tissues, or the specific protein interacting with AMCase, in which the complex directly or indirectly initiating the signaling leading to the asthmatic inflammation. Since the current therapy of asthma mainly focus on treating bronchospasms and airway inflammation. The obtained results would not only provide a better molecular understanding of asthma, but also couple to the development of a promising therapeutic strategy for asthma by silencing AMCase expression.

Project ID:PC9902-1649
External Project ID:NSC98-2320-B182-014-MY3