YKL-40 in Idiopathic Pulmonary Fibrosis and Kidney Transplantation

描述(申请人提供)：糖基水解酶18(GH18)基因家族包含进化上保守的几丁质酶样蛋白(CLP)，被认为在生物学中发挥重要作用。然而，它们的功能特征才刚刚开始被调查。我们最近证实，原型CLP(人的YKL-40和小鼠的BRP-39)是细胞凋亡、M2巨噬细胞激活、转化生长因子-β的合成和组织纤维化的循环调节因子。我们还确定了任何GH18部分的第一个受体，IL-13受体(R)a2。对特发性肺纤维化(IPF)患者的研究显示，血浆YKL-40水平升高与不良结局相关。移植肾功能延迟恢复(DGF)患者移植后尿YKL-40水平升高。这些发现使我们推测：(A)YKL-40水平升高是IPF和DGF风险分层的生物标志物；(B)YKL-40由上皮细胞和巨噬细胞产生，并通过IL-13Ra2刺激转化生长因子-β1和M2巨噬细胞激活而介导其作用；(C)YKL-40和IL-13Ra2是IPF和DGF的治疗靶点。为了验证这一假设，我们将评估YKL-40作为生物标记物在两个不同的患者队列中的作用，一个患者患有IPF，另一个患者患有DGF。我们还将评估其用于调节其细胞效应的机制，以及YKL-40/BRP-39和IL-13Ra2作为这些疾病的治疗靶点的有效性。我们会的；目标1。确定循环中YKL-40的水平及其在IPF中作为生物标志物的作用。目的2.明确循环和尿液中YKL-40的水平及其作为DGF生物标志物的作用。目的3.鉴定YKL-40在IPF和DGF中的定位和分子图谱。目的4.研究YKL-40、IL-13Ra2和转化生长因子-31之间的相互关系以及YKL-40调节单核细胞系细胞在IPF和DGF中聚集的能力。目的5.探讨BRP-39和IL-13Ra2在小鼠肺纤维化和缺血再灌注肾损伤模型中的作用。相关性(参见说明)：我们已经确定了几丁质酶样蛋白YKL-40与人类两种不同形式的适应不良修复之间的关系。肾移植后特发性肺纤维化与移植肾功能延迟。在这笔赠款中，我们将探索YKL-40作为这些疾病进展预测因子的用途，确定YKL-40对纤维化发挥作用的机制，并确定这一途径是否是这些疾病中的一种或两种疾病的治疗靶点。(摘要结束)

DESCRIPTION (provided by applicant): The glycosyl hydrolase 18 (GH18) gene family contains evolutionarily conserved chitinase-like proteins (CLP) that are presumed to play essential roles in biology. However, their functional profiles have just begun to be investigated. We recently demonstrated that the prototypic CLP (YKL-40 in man and BRP-39 in the mouse) is a circulating regulator of apoptosis, alternative (M2) macrophage activation and TGF-bi elaboration and tissue fibrosis. We also identified the first receptor for any GH18 moiety, IL-13 receptor(R)a2. Studies of patients with idiopathic pulmonary fibrosis (IPF) revealed elevated levels of plasma YKL-40 that correlated with adverse outcomes. After kidney transplant, urinary YKL-40 levels were increased in patients with delayed graft function (DGF). These findings led us to hypothesize that (a) elevated levels of YKL-40 are biomarkers of risk-stratification in IPF and DGF; (b) YKL-40 is produced by epithelial cells and macrophages and mediates its effects by stimulating TGF-b1 and M2 macrophage activation via IL-13Ra2; (c) YKL-40 and IL-13Ra2 are therapeutic targets in IPF and DGF. To test this hypothesis we will evaluate YKL-40 as a biomarker in two separate cohorts of patients, one with IPF and one with DGF. We will also evaluate the mechanisms it uses to mediate its cellular effects and the utility of YKL-40/BRP-39 and IL-13Ra2 as therapeutic targets in these disorders. We will; Aim 1. Define the levels of circulating YKL-40 and their roles as biomarkers in IPF. Aim 2. Define the levels of circulating & urinary YKL-40 and their roles as biomarkers in DGF. Aim 3. Characterize the location and molecular profile of YKL-40 in IPF and DGF. Aim 4. Characterize the relationships between YKL-40, IL-13Ra2 and TGF-|31 and the ability of YKL-40 to regulate monocyte lineage cell fate and accumulation in IPF and DGF. Aim 5. Characterize the roles of BRP-39 and IL-13Ra2 in murine lung fibrosis and ischemia/reperfusion kidney injury models. RELEVANCE (See instructions): We have identified a relationship between the chitinase-like protein YKL-40 and two different forms of maladaptive repair in humans. Idiopathic Pulmonary Fibrosis and Delayed Graft Function following renal transplantation. In this grant we will explore the utility of YKL-40 to serve as a predictor of progression in these diseases, define the mechanism through which YKL-40 exerts its effects on fibrosis, and determine whether this pathway is a therapeutic target in one or both of these diseases. (End of Abstract)