Understanding the role of AMCase in asthma

描述(申请人提供)：哮喘的特征是慢性呼吸道炎症。众所周知，Th2炎症及其下游反应为哮喘的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清除寄生虫和真菌。因此，哮喘的免疫反应被认为是一种错误的抗寄生虫反应。甲壳素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，其作用似乎是保护它们免受环境中的有害事件的影响，例如捕食者。降解几丁质的酶，几丁质酶，是由表达几丁质的生物和寄生虫的宿主编码的。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，但所有被研究的哺乳动物都编码几丁质酶。最近的研究表明，哺乳动物基因组中编码了大量的几丁质酶及其相关基因。虽然这些基因中的一些编码具有酶活性的真正的几丁质酶，但另一些基因具有结合但不能水解几丁质的能力。根据所研究的模型，几丁质酶和几丁质已被证明既可以诱导过敏性哮喘，也可以抑制过敏性哮喘。在这个项目中，我们将通过建立和表征具有几丁质和非几丁质呼吸道暴露模型的条件基因敲除AMCase小鼠来定义AMCase的功能，AMCase是一种具有真正酶活性的几丁质酶。此外，我们将使用一种新的AMCase敲击鼠来阐明AMCase酶活性和几丁质结合活性在哮喘小鼠模型中的作用，该小鼠失去了酶活性，同时保留了几丁质结合功能。控制哮喘等疾病是美国医疗保健系统面临的一项重大挑战。本申请中提出的工作应有助于更好地理解导致免疫反应意外激活的事件，从而导致免疫病理学。此外，这笔资金将允许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，并保留一名，并雇用第二名博士后助理。 公共卫生相关性：我们的实验室有针对AMCase的有条件的小鼠，以及有酶缺陷的AMCase敲击的小鼠。因此，我们处于一个独特的位置来测试AMCase在肺部疾病中的作用，并进一步确定AMCase的几丁质酶活性是否以及如何影响这种反应。

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.