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

说明（由申请人提供）：人体内不存在几丁质和几丁质合成酶。然而，几丁质酶和几丁质酶样蛋白（C/CLP）最近得到了重视。这包括真正的几丁质酶和缺乏几丁质酶活性的部分，如乳腺消退蛋白39 （BRP-39）及其人类同源物YKL-40。BRP-39和YKL-40在多种疾病中以夸张的方式表达。然而，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在变应性炎症中的调控作用。这些研究表明(a) BRP-39在Th2和il -13诱导的炎症部位显著诱导，(b) BRP-39-/-小鼠在Th2和il -13诱导的炎症和重塑中存在显著缺陷，这与T细胞和巨噬细胞凋亡和Fas表达增强有关，(c) BRP-39/ ykl -40诱导的细胞保护与蛋白激酶b /Akt活化增强有关。他们还证明BRP-39/YKL-40结合IL-13受体(R)a2，并通过IL-13Ra2依赖机制激活有丝分裂原活化蛋白激酶（MAPK）和PKB/Akt。最后，他们通过证明YKL-40在严重哮喘患者的血清和肺部中含量过高，以及几丁质酶3样1是哮喘易感基因，强调了这些发现与人类的相关性。这就引出了下面的假设。假设:1。BRP-39/YKL-40在适应性Th2炎症和重塑的发病过程中受到诱导，并在其发病机制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。为了验证这一假设，我们提出：AIM 1。表征BRP-39在Th2和Th1炎症和重塑中的表达和作用。目标2。表征血清、组织、上皮和巨噬细胞来源的BRP-39/YKL-40在Th2和il -13诱导的炎症和重塑中的相对贡献。目标3。明确BRP-39/YKL-40与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。目标4。描述BRP-39-/-小鼠中夸大的T细胞和巨噬细胞凋亡/细胞死亡反应的机制以及这种细胞死亡途径与人类的相关性。

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.