Role of Lipocalin 2 Inflammatory Bowel Disease

描述（由申请人提供）：炎症性肠病（IBD）是肠道慢性特发性炎症性疾病的统称，最著名的是克罗恩病（CD）和溃疡性结肠炎（UC），这两种疾病在美国和欧洲分别影响140万人和220万人。IBD与一些驱动或抑制炎症反应的急性期蛋白（APP）水平升高有关。对APP生物活性的探索促进了靶向生物治疗剂的开发。事实上，直接拮抗促炎介质或模拟抗炎分子的药物目前正在使用和/或开发用于治疗IBD。然而，一些最动态调节的APP的生物活性和治疗潜力仍未被探索。例如，虽然APP脂载素-2 （Lcn2）水平在各种炎症条件下增加了几个对数数量级，包括小鼠结肠炎和人类IBD，但Lcn2在多大程度上驱动或抑制肠道炎症仍未被探索。除了与结肠炎相关的表达升高外，Lcn2（以及其人类同源物中性粒细胞明胶酶相关脂脂蛋白）或NGAL的多面生物活性表明，它可能在IBD中发挥核心作用。具体来说，Lcn2具有很强的抗菌活性

DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD) is the collective term for chronic idiopathic inflammatory diseases of the intestine, most notably Crohn's Disease (CD) and Ulcerative Colitis (UC), which together affect 1.4 million people in the US and 2.2 million people in Europe. IBD is associated with elevated levels of a number of acute phase proteins (APP) that drive or dampen the inflammatory response. Exploration of the biologic activities of APP has resulted in the development of targeted biological therapeutic agents. Indeed, agents that directly antagonize pro-inflammatory mediators or mimic anti-inflammatory molecules are currently being used and/or developed to treat IBD. However, the biologic activity, and thus therapeutic potential, of some of the most dynamically regulated APP remain unexplored. For example, while levels of the APP lipocalin-2 (Lcn2) increase by several log orders of magnitude in various inflammatory conditions, including murine colitis and human IBD, the extent to which Lcn2 drives or dampens gut inflammation remains unexplored. In addition to its elevated expression being associated with colitis, the multifaceted biologic activity of Lcn2 (as well as that of its human ortholog, Neutrophil Gelatinase-Associated Lipocalin) or NGAL suggests it may play a central role in IBD. Specifically, Lcn2 exerts potent antibacterial activity mediated by sequestering bacterial siderophores and thereby preventing bacteria from scavenging iron from lower affinity host proteins. In addition, Lcn2 participates in iron transport stabilizing highly reactive catalytic iron by chelation. Accordingly, it has been shown that Lcn2 deficient mice are highly susceptible to bacterial and LPS-induced sepsis. We hypothesize that Lcn2's control over iron homeostasis is not limited to the extreme events such as sepsis but, rather, that the dynamic regulation of Lcn2 from low-grade inflammation to acute and chronic colitis plays an important role in preserving gut neutrophil function as well as iron/microbiota homeostasis. Consequently, the goal of this proposal is to investigate the role and mechanism of action of Lcn2 in intestinal inflammation. Establishing the role of this dynamically regulated protein will advance our knowledge of pathogenesis and perhaps allow development of novel therapeutic strategies to treat human IBD. We anticipate that these studies will demonstrate a key role for Lcn2 in protecting the gut. Given its small size, simple structure and biologic activiy in the absence of post-translational modification, Lcn2 may be exploitable as a treatment for intestinal inflammation.