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: 8207985
• 负责人: Jack A Elias
• 金额: $ 40.96万
• 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 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8207985
• 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. PUBLIC HEALTH RELEVANCE: Our studies demonstrated that a protein named BRP-39 plays a critical role in asthma-like inflammation in the mouse and that the human equivalent, YKL-40, is found in exaggerated quantities in the circulation of people with severe asthma. They also demonstrated that BRP-39/YKL-40 likely mediates its biologic effects by controlling the death of inflammatory cells. This proposal will investigate the processes that regulate the production of this molecule and define the receptor, signaling pathways and mechanisms that it uses to regulate cell death.

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。 公共健康相关性：我们的研究表明，一种名为 BRP-39 的蛋白质在小鼠哮喘样炎症中发挥着关键作用，而人类等效蛋白质 YKL-40 在严重哮喘患者的循环中含量过高。他们还证明，BRP-39/YKL-40 可能通过控制炎症细胞的死亡来介导其生物效应。该提案将研究调节该分子产生的过程，并定义其用于调节细胞死亡的受体、信号传导途径和机制。