Understanding the role of AMCase in asthma

了解 AMCase 在哮喘中的作用

• 批准号: 7818950
• 负责人: Richard A. Flavell
• 金额: $ 50万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7818950
• 关键词: Address; Affect; Allergens; Asthma; Binding; Breathing; Carbohydrates; Chin; Chitin; Chitinase; Chronic; Conflict (Psychology); Crustacea; Data; Development; Environment; Enzymes; Epithelial Cells; Event; Exposure to; Extrinsic asthma; Funding; Genes; Hand; Healthcare Systems; Human; Hydrolysis; Immune response; Immunologic Adjuvants; In Vitro; Infection; Infectious Agent; Inflammation; Inflammatory; Inflammatory Response; Knock-out; Knockout Mice; Laboratories; Lead; Left; Literature; Lung; Lung diseases; Mammals; Mediating; Modeling; Mus; Organism; Parasites; Pathogenesis; Planets; Play; Pneumonia; Positioning Attribute; Protein Binding; Pyroglyphidae; Role; Study models; Testing; Work; airway inflammation; allergic airway inflammation; base; disorder control; fungus; immunopathology; in vivo; macrophage; mammalian genome; novel; pathogen; prevent; public health relevance; response

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.

描述（由申请人提供）：哮喘的特征是慢性气道炎症。众所周知，Th2炎症和发生的下游反应提供了哮喘发病机制的许多潜在基础。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。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细胞壁中，它的作用似乎是保护它们免受环境中有害事件的影响，如捕食者。降解几丁质的酶，几丁质酶，由表达几丁质的生物体以及寄生虫的宿主编码。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体的先天免疫应答中起重要作用。哺乳动物，包括人类，不合成几丁质，但所有研究的哺乳动物编码几丁质酶。近年来的研究表明，哺乳动物基因组中编码有大量几丁质酶及几丁质酶相关基因。虽然这些基因中的一些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，我们将定义的功能AMCase，几丁质酶与真正的酶活性，通过生成和表征条件敲除AMCase小鼠与几丁质和非几丁质气道暴露模型。此外，我们将阐明AMCase酶活性以及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基因敲入小鼠，酶活性丧失，同时保留几丁质结合功能。控制哮喘等疾病是美国卫生保健系统面临的关键挑战。本申请中提出的工作应能更好地了解导致免疫应答意外激活的事件，从而导致免疫病理学。此外，这笔资金将允许继续支持一个非常有才华的技术人员，否则他们将不得不离开和保留一个和雇用第二个博士后助理。 公共卫生相关性：我们的实验室有条件地靶向AMCase的小鼠以及敲入酶缺陷型AMCase的小鼠。因此，我们处于独特的位置来测试AMCase在肺部疾病中的作用，并且确定AMCase的几丁质酶活性是否以及如何影响这种反应。