YKL-40 in Idiopathic Pulmonary Fibrosis and Kidney Transplantation

描述（由申请人提供）：糖基水解酶18（GH 18）基因家族包含进化上保守的几丁质酶样蛋白（CLP），推测其在生物学中发挥重要作用。然而，他们的功能配置文件刚刚开始进行调查。我们最近证明，原型CLP（人中的YKL-40和小鼠中的BRP-39）是细胞凋亡、替代（M2）巨噬细胞活化和TGF-β 1加工和组织纤维化的循环调节剂。我们还鉴定了任何GH 18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。肾移植后，移植肾功能延迟恢复（DGF）患者尿YKL-40水平升高。这些发现使我们假设：（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-13 Ra 2刺激TGF-β 1和M2巨噬细胞活化介导其作用;（c）YKL-40和IL-13 Ra 2是IPF和DGF的治疗靶点。为了检验这一假设，我们将在两个单独的患者队列（一个患有IPF，一个患有DGF）中评估YKL-40作为生物标志物。我们还将评估其用于介导其细胞效应的机制以及YKL-40/BRP-39和IL-13 Ra 2作为这些疾病中的治疗靶点的效用。我们会的;目标1.定义循环YKL-40的水平及其作为IPF生物标志物的作用。目标2.定义循环和尿液YKL-40的水平及其作为DGF生物标志物的作用。目标3。描述IPF和DGF中YKL-40的位置和分子特征。目标4。表征YKL-40、IL-13 Ra 2和TGF-β 1之间的关系。|图31和YKL-40调节IPF和DGF中单核细胞谱系细胞命运和积累的能力。目标5。表征BRP-39和IL-13 Ra 2在鼠肺纤维化和缺血/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和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和移植肾功能延迟恢复。在这项资助中，我们将探索YKL-40作为这些疾病进展的预测因子的效用，定义YKL-40对纤维化发挥作用的机制，并确定该途径是否是这些疾病之一或两者的治疗靶点。(End摘要）

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)