Role of Lipocalin 2 Inflammatory Bowel Disease

描述(申请人提供)：炎症性肠病(IBD)是慢性特发性肠道炎症性疾病的统称，最著名的是克罗恩病(CD)和溃疡性结肠炎(UC)，美国有140万人受到影响，欧洲有220万人受到影响。炎症性肠病与多种急性时相蛋白(APP)水平升高有关，这些APP可驱动或抑制炎症反应。对APP生物活性的探索导致了靶向生物治疗药物的开发。事实上，目前正在使用和/或开发直接拮抗促炎介质或模拟抗炎分子的药物来治疗IBD。然而，一些动态调控的APP的生物活性和治疗潜力仍未被探索。例如，尽管APP Lipocalin-2(Lcn2)的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促进或抑制肠道炎症的程度仍未被探索。除了它的高表达与结肠炎有关外，Lcn2(以及它的人类同源基因，中性粒细胞明胶酶相关的Lipocalin)或NGAL的多方面生物学活性表明，它可能在IBD中发挥核心作用。具体地说，Lcn2具有很强的抗菌活性 通过隔离细菌铁载体，从而防止细菌从低亲和力宿主蛋白中清除铁。此外，LCN2还通过络合作用参与铁的转运，稳定高活性的催化铁。因此，研究表明，Lcn2缺陷小鼠对细菌和内毒素诱导的脓毒症高度敏感。我们推测，LCN2的S对铁稳态的调控并不局限于脓毒症等极端事件，而是LCN2从低度炎症到急慢性结肠炎的动态调节在维持肠道中性粒细胞功能和铁/微生物区系稳态方面发挥着重要作用。因此，本研究的目的是研究Lcn2在肠道炎症中的作用和作用机制。确定这种动态调节蛋白的作用将促进我们对发病机制的了解，并可能开发新的治疗策略来治疗人类IBD。我们预计这些研究将证明Lcn2在保护肠道中的关键作用。由于Lcn2体积小，结构简单，在没有翻译后修饰的情况下具有生物活性，因此可能被开发为一种治疗肠道炎症的药物。

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.