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

描述(申请人提供)：人类体内不存在甲壳素和甲壳素合成酶。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，如乳房回归蛋白-39(BRP-39)及其人类同源物YKL-40。BRP-39和YKL-40在多种疾病中以夸大方式表达。然而，对于它们在哺乳动物或人类生物学中的作用，人们几乎一无所知。我们研究了BRP-39在变态反应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明显缺陷，这与T细胞和巨噬细胞凋亡和Fas表达增加有关，(C)BRP-39/YKL-40诱导的细胞保护与蛋白激酶B/Akt激活有关。它们还证明了BRP-39/YKL-40与IL-13受体(R)a2结合，并通过IL-13Ra2依赖的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与人类的相关性，证明了在严重哮喘患者的血清和肺中发现了夸大的YKL-40数量，并且几丁质酶3-样1是哮喘的易感基因。这让我们得出了以下假设。假设：1.BRP-39/YKL-40在适应性Th2炎症和重构的发病过程中被诱导，并在其中起关键和选择性的作用。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通过参与IL-13Ra2、MAPK和/或PKB/Akt的途径(S)介导其组织反应。为了验证这一假说，我们建议：目的1.鉴定BRP-39在Th2和Th1炎症和重塑中的表达和作用。目的2.研究血清和组织及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作用。目的3.明确BRP-39/YKL-40与IL-13Ra2的相互作用以及IL-13Ra2在BRP-39/YKL-40生物学效应发生机制中的作用。目的4.研究BRP-39-/-小鼠T细胞和巨噬细胞凋亡/细胞死亡反应增强的机制及其与人类的关系。 公共卫生相关性：我们的研究表明，一种名为BRP-39的蛋白质在小鼠的哮喘样炎症中发挥关键作用，而人类的等价物YKL-40在严重哮喘患者的血液循环中被夸大了。他们还证明，BRP-39/YKL-40可能通过控制炎症细胞的死亡来调节其生物学效应。这项提议将研究调节这种分子产生的过程，并定义它用来调节细胞死亡的受体、信号通路和机制。

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.