Understanding the role of AMCase in asthma

描述（由申请人提供）：哮喘以慢性气道炎症为特征。众所周知，Th2炎症和发生的下游反应为哮喘发病提供了许多潜在的基础。Th2炎症的生物学功能被认为是识别和消除寄生虫和真菌。因此，哮喘免疫反应被认为是一种错误的抗寄生虫反应。几丁质是地球上第二丰富的碳水化合物。它存在于寄生虫、甲壳类动物和真菌的壁上，它的作用似乎是保护它们免受环境中有害事件的侵害，比如捕食者。降解几丁质的酶，几丁质酶，是由表达几丁质的生物体以及寄生虫宿主编码的。因此，几丁质酶被认为在对寄生虫、真菌和其他表达几丁质的感染性生物的先天免疫反应中发挥重要作用。哺乳动物，包括人类，不合成几丁质，但所有研究的哺乳动物都编码几丁质酶。近年来的研究表明，哺乳动物基因组中编码了大量几丁质酶和几丁质酶相关基因。虽然其中一些基因编码具有酶活性的真正几丁质酶，但其他基因具有结合但不能水解几丁质的能力。几丁质酶和几丁质已被证明可以诱导和抑制过敏性哮喘的特征，这取决于所研究的模型。在这个项目中，我们将定义AMCase的功能，AMCase是一种具有真正酶活性的几丁质酶，通过在几丁质和非几丁质气道暴露模型中产生和表征条件敲除AMCase小鼠。我们将进一步阐明AMCase酶活性和几丁质结合活性在哮喘小鼠模型中的作用，使用一种新的AMCase敲入小鼠，其酶活性丧失，但保留了几丁质结合功能。哮喘等疾病的控制是美国卫生保健系统面临的关键挑战。本应用程序中提出的工作应提供对导致免疫反应意外激活导致免疫病理的事件的更好理解。此外，这笔资金将继续支持一名非常有才华的技术人员，否则他们将不得不离开，保留一名并雇用第二名博士后。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.