Asthma is characterized by chronic airway inflammation. It is well established that Th2 inflammation and the downstream responses that occur provide much of the underlying basis of asthma pathogenesis. The biologic function of Th2 inflammation is believed to be the recognition and elimination of parasites and fungi. As such, the asthmatic immune response is thought to be a misdirected anti-parasite response. Chitin is the second-most abundant carbohydrate of our planet. It is found in the walls of parasites, crustaceans and fungi, and its role seems to be to protect them from noxious events in their environment, such as predators. The enzymes that degrade chitin, chitinases, are encoded by organisms that express chitin as well as the hosts of parasites. Chitinase is therefore believed to play an essential role in the innate immune response to parasites, fungi and other chitin expressing infectious organisms. Mammals, including humans, do not synthesize chitin but all mammals studied encode chitinases. Recent studies have shown that a large number of chitinase and chitinase-related genes are encoded in the mammalian genome. While some of these genes encode true chitinases that have enzymatic activity, others have the ability to bind but not to hydrolyze chitin. Chitinases and chitin have been shown to both induce and inhibit features of allergic asthma, depending on the model studied. In this project we will define the function of AMCase, a chitinase with true enzymatic activity by generating and characterizing conditional knockout AMCase mice with both chitin and non-chitin airway exposure models. Further we will elucidate the role of AMCase enzymatic activity as well as chitin binding activity in a murine model of asthma using a novel AMCase knockin mouse with a loss of enzymatic activity while preserving the chitin-binding function. Control of diseases such as Asthma is a critical challenge for the health care system in the U.S. Work proposed in this application should provide a better understanding of the events leading to the unintended activation of the immune response leading to immunopathology. In addition, this funding will allow continued support for a very talented technician, who would otherwise have to leave and retention of one and hiring of a second postdoctoral associate.
Our laboratory has in hand mice conditionally targeted for AMCase as well as mice with a knockin of an enzymatically defective AMCase. For that reason we are in a unique position to test the role of AMCase in lung disease and, moreover to determine if and how the chitinase activity of AMCase affects this response.
|Kim, Lark Kyun; Morita, Rimpei; Kobayashi, Yasushi et al. (2015) AMCase is a crucial regulator of type 2 immune responses to inhaled house dust mites. Proc Natl Acad Sci U S A 112:E2891-9|