BRP-39/YKL-40 in Th2 Inflammation and Asthma

BRP-39/YKL-40 在 Th2 炎症和哮喘中的作用

• 批准号: 8402992
• 负责人: Jack A Elias
• 金额: $ 23.31万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-18 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8402992
• 关键词: Acute; Address; Allergic inflammation; Animals; Antifungal Agents; Antigens; Apoptosis; Area; Aspergillus; Asthma; Binding; Binding Sites; Biology; Blood Circulation; Breast; Breeding; CHI3L1 gene; Cell Death; Cells; Cessation of life; Chitin; Chitin Synthase; Chitinase; Chronic; Cleaved cell; Crustacea; Cytoprotection; Defect; Disease; Enzymes; Epithelial; Epithelial Cells; Evaluation; Event; Family; Family member; Genetic Polymorphism; Health; Homologous Gene; Human; Human Biology; Hydrolase; IgE; Immune Sera; In Vitro; Inflammation; Inflammatory; Interferons; Interleukin-13; Knowledge; Laboratories; Life Cycle Stages; Lung; Mediating; Messenger RNA; Mitogen Activated Protein Kinase 1; Mitogen-Activated Protein Kinases; Modeling; Mus; Mutation; Names; Parasites; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Process; Production; Proteins; Proto-Oncogene Proteins c-akt; Reaction; Receptor Signaling; Recombinants; Regulation; Relative (related person); Research; Respiratory physiology; Role; Serum; Severity of illness; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; Susceptibility Gene; T-Lymphocyte; TNFRSF6 gene; Testing; Tissues; Transgenic Mice; Transgenic Organisms; acidic mammalian chitinase; antigen challenge; cytokine; defined contribution; extracellular signal-regulated kinase 3; fungus; in vivo; insight; macrophage; man; null mutation; overexpression; prototype; public health relevance; receptor; research study; response; selective expression

DESCRIPTION (provided by applicant): Chitin and chitin synthase do not exist in man. However, chitinases and chitinase-like proteins (C/CLP) have recently been appreciated. This includes true chitinases and moieties that lack chitinase activity like breast regression protein-39 (BRP-39) and its human homologue YKL-40. BRP-39 and YKL-40 are expressed in an exaggerated fashion in a variety of diseases. However, virtually nothing is known about their roles in mammalian or human biology. We studied the regulation and roles of BRP-39 in allergic inflammation. These studies demonstrate that (a) BRP-39 is prominently induced at sites of Th2 and IL-13-induced inflammation, (b) BRP-39-/- mice have a significant defect in Th2 and IL-13-induced inflammation and remodeling that is associated with enhanced T cell and macrophage apoptosis and Fas expression and (c) BRP-39/YKL-40-induced cytoprotection is associated with enhanced protein kinase B/Akt activation. They also demonstrate that BRP-39/YKL-40 binds to IL-13 receptor (R)a2 and activates mitogen activated protein kinases (MAPK) and PKB/Akt via an IL-13Ra2- dependent mechanism. Lastly, they highlight the human relevance of these findings by demonstrating that YKL-40 is found in exaggerated quantities in the serum and lungs from severe asthmatics and that chitinase 3- like 1 is an asthma susceptibility gene. This led us to the following hypothesis. HYPOTHESIS: 1. BRP-39/YKL-40 is induced during and plays a critical and selective role in the pathogenesis of adaptive Th2 inflammation and remodeling. 2. BRP-39 and YKL-40 are important regulators of T cell and macrophage apoptosis/cell death. 3. BRP-39 and YKL-40 mediate their tissue responses via a pathway(s) that involves IL-13Ra2, MAPK and or PKB/Akt. To test this hypothesis we propose to: AIM 1. Characterize the expression and roles of BRP-39 in Th2 and Th1 inflammation and remodeling. AIM 2. Characterize the relative contributions of serum and tissue and epithelial- and macrophage-derived BRP-39/YKL-40 in Th2 and IL-13-induced inflammation and remodeling. AIM 3. Define the interactions of BRP-39/YKL-40 and IL-13Ra2 and the roles of IL-13Ra2 in the pathogenesis of the biologic effects of BRP-39/YKL-40. AIM 4. Characterize the mechanisms of the exaggerated T cell and macrophage apoptosis/cell death responses in BRP-39-/- mice and the relevance of this cell death pathway to humans.

描述（由申请人提供）： 人体中不存在甲壳素和甲壳素合酶。然而，几丁质酶和几丁质酶样蛋白（C/CLP）最近受到重视。这包括真正的几丁质酶和缺乏几丁质酶活性的部分，如乳腺退化蛋白 39 (BRP-39) 及其人类同源物 YKL-40。 BRP-39 和 YKL-40 在多种疾病中以过度表达的方式表达。然而，人们对它们在哺乳动物或人类生物学中的作用几乎一无所知。我们研究了 BRP-39 在过敏性炎症中的调节和作用。这些研究表明，(a) BRP-39 在 Th2 和 IL-13 诱导的炎症位点显着被诱导，(b) BRP-39-/- 小鼠在 Th2 和 IL-13 诱导的炎症和重塑方面存在显着缺陷，这与 T 细胞和巨噬细胞凋亡和 Fas 表达增强相关，(c) BRP-39/YKL-40 诱导 细胞保护与增强的蛋白激酶 B/Akt 激活相关。他们还证明，BRP-39/YKL-40 与 IL-13 受体 (R)a2 结合，并通过 IL-13Ra2 依赖性机制激活丝裂原激活蛋白激酶 (MAPK) 和 PKB/Akt。最后，他们强调了这些发现的人类相关性，证明 YKL-40 在严重哮喘患者的血清和肺部中含量过高，并且几丁质酶 3-like 1 是一种哮喘易感基因。这导致我们得出以下假设。假设： 1. BRP-39/YKL-40 在适应性 Th2 炎症和重塑的发病机制中被诱导，并在其中发挥关键和选择性作用。 2. BRP-39和YKL-40是T细胞和巨噬细胞凋亡/细胞死亡的重要调节因子。 3. BRP-39 和 YKL-40 通过涉及 IL-13Ra2、MAPK 和/或 PKB/Akt 的途径介导其组织反应。为了检验这一假设，我们建议： 目标 1. 表征 BRP-39 在 Th2 和 Th1 炎症和重塑中的表达和作用。目的 2. 表征血清和组织以及上皮细胞和巨噬细胞来源的 BRP-39/YKL-40 在 Th2 和 IL-13 诱导的炎症和重塑中的相对贡献。目的 3. 明确 BRP-39/YKL-40 和 IL-13Ra2 的相互作用以及 IL-13Ra2 在 BRP-39/YKL-40 生物学效应发病机制中的作用。目的 4. 描述 BRP-39-/- 小鼠中 T 细胞和巨噬细胞凋亡/细胞死亡反应过度的机制以及该细胞死亡途径与人类的相关性。